Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

At present, nine small-molecule MDM2 inhibitors belonging to different structural types have entered clinical trials.

“At present, nine small-molecule MDM2 inhibitors belonging to different structural types have entered clinical trials (Table 1).”

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RG7112 (25-200 mg/kg, oral administration) activated the p53 pathway in vivo and induced apoptosis of tumor cells; RG7112 (100 mg/kg, once a day, 5 days/week, for 3 weeks) reduced tumor growth rate and improved survival rate in the GBM model.

“In vivo experiments showed that RG7112 (25 ~ 200 mg/kg, oral administration) activated the p53 pathway in vivo and induced apoptosis of tumor cells. RG7112 (100 mg/kg−1, once a day, 5 days/week, for 3 weeks) reduced the tumor growth rate and improve the survival rate in the GBM model [24].”

• cites [24] Verreault M, Schmitt C, Goldwirt L, et al. Preclinical efficacy of the MDM2 inhibitor RG7112 in MDM2-amplified and TP53 wild-type glioblastomas. Clin Cancer Res. 2016;22(5):1185–96. sourceNot checked yet

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The cocrystal structure of the N-terminal transcriptional activation region of MDM2 and p53 protein showed that the binding surface area of p53 and MDM2 was small and there was an obvious binding cavity.

“The cocrystal structure of the N-terminal transcriptional activation region of MDM2 and p53 protein showed (PDB: 1YCR, Fig. 2) that the binding surface area of p53 and MDM2 protein was small, and there was an obvious binding cavity.”

• cites [14] Kussie PH, Gorina S, Marechal V, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996;274(5289):948–53. sourceNot checked yet

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After inactivation of the TP53 gene in mice, cells lacking functional p53 cannot respond appropriately to external stimuli, resulting in a high probability of tumors.

“Studies have revealed that after inactivation of the TP53 gene (encoding p53) in mice, cells lacking functional p53 cannot respond appropriately to external stimuli, resulting in a high probability of tumors [7].”

• cites [7] Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356(6366):215–21. sourceNot checked yet

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In a phase I clinical trial for leukemia patients, RG7112 treatment improved the expression level of p53 and downstream genes; in 30 patients, five cases of CR or PR and nine cases of SD were observed.

“Another phase I clinical trial for leukemia patients also proved that RG7112 treatment can improve the expression level of p53 and downstream genes. In 30 patients, five cases of CR or PR and nine cases of SD were observed [26].”

• cites [26] Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22(4):868–76. sourceNot checked yet

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MI-888 binding activity to MDM2 was Ki = 0.44 nM; its inhibitory activity against tumor cells was at nM level in SJSA-1 and RS4;11 cells, with high selectivity for wild-type p53 over mutant or knockout p53 tumor cells and no significant toxic side effects.

“At the same time, its polar tail extending into the solvent region can further improve its PK parameters in vivo and its binding ability to MDM2 protein (Ki = 0.44 nM). Its inhibitory activity against tumor cells was at the nM level in SJSA-1 and RS4;11 cells, and the selectivity for wild-type p53 over mutant or knockout p53 tumor cells was high, without significant toxic side effects [39].”

• cites [39] Zhao Y, Yu S, Sun W, et al. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J Med Chem. 2013;56(13):5553–61. sourceNot checked yet

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Classified as probably not a substantial claim.

No MDM2 inhibitor has been approved for clinical application.

“However, no MDM2 inhibitor has been approved for clinical application.”

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In a phase III clinical trial (NCT02545283) of RG7388 in combination with cytarabine for relapsed or refractory AML, preliminary results showed complete remission rate reached 25%, median remission time approximately 6.4 months, related to MDM2 protein level before treatment; the study was discontinued due to unexpected results.

“The preliminary results showed that the complete remission rate reached 25%, and the median remission time was approximately 6.4 months, which was related to the level of MDM2 protein before treatment [32]. However, the study was discontinued due to unexpected results.”

• cites [32] Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther. 2019;12:2903–10. sourceNot checked yet

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Nutlin-3a had the strongest activity, and its binding activity with MDM2 reached 90 nM.

“Nutlin-3a had the strongest activity, and its binding activity with MDM2 reached 90 nM.”

• cites [20] Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303(5659):844–8. sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

The MDM2 protein directly regulates the expression of p53 protein through negative feedback.

“The MDM2 protein is widely studied because it can directly regulate the expression of p53 protein through negative feedback.”

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In the SJSA xenograft model of mice, RG7388 (25 mg/kg, oral administration) led to tumor growth inhibition and regression, and induced apoptosis and antiproliferative effects.

“In the SJSA xenograft model of mice, RG7388 (25 mg/kg, oral administration) led to tumor growth inhibition and regression, and induced apoptosis and antiproliferative effects [31].”

• cites [31] Higgins B, Glenn K, Walz A, et al. Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. Clin Cancer Res. 2014;20(14):3742–52. sourceNot checked yet

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MDM2 has a RING domain that promotes transfer of p53 from nucleus to cytoplasm and reduces its nuclear accumulation, leading to disappearance of p53 transcription function.

“Second, the MDM2 protein has a unique RING domain, which can promote the transfer of p53 protein from the nucleus to the cytoplasm and reduce its accumulation in the nucleus, leading to the disappearance of p53 protein transcription function.”

• cites [11] Hock AK, Vousden KH. The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta. 2014;1843(1):137–49. sourceNot checked yet

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• cites [12] Bang S, Kaur S, Kurokawa M. Regulation of the p53 family proteins by the ubiquitin proteasomal pathway. Int J Mol Sci. 2019;21(1):261. sourceNot checked yet

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• cites [13] do Patrocinio AB, Rodrigues V, Guidi Magalhães L. P53: Stability from the Ubiquitin-Proteasome System and Specific 26S Proteasome Inhibitors. ACS Omega. 2022;7(5):3836–3843. sourceNot checked yet

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Phase I studies demonstrated improved pharmacokinetic parameters of RG7388 for advanced solid tumors and AML, but its safety was comparable to that of RG7388 and did not show sufficient advantages.

“Although phase I studies demonstrated improved pharmacokinetic parameters of RG7388 for advanced solid tumors and AML, its safety was comparable to that of RG7388 and did not show sufficient advantages [34, 35].”

• cites [34] Abdul Razak AR, Miller WH Jr, Uy GL, et al. A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors. Investig New Drugs. 2020;38(4):1156–65. sourceNot checked yet

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• cites [35] Uy GL, Assouline S, Young AM, et al. Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia. Investig New Drugs. 2020;38(5):1430–41. sourceNot checked yet

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Multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity.

“Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53–MDM2 interaction”

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RG7112 had a stronger binding ability to MDM2 than Nutlin-3a with enhanced cell activity and better pharmacokinetic parameters, making it more suitable for clinical trials.

“Finally, through the activity and pharmacokinetic evaluations, it was determined that RG7112 had a stronger binding ability to MDM2 than Nutlin-3a with an enhanced cell activity and better pharmacokinetic parameters, making it more suitable for clinical trials.”

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Nutlin-3a's antiproliferative activity against wild-type p53 inactivated tumor cells (HCT116, RKO and SJSA-1) is 1-2 μM, but its activity against mutant p53 tumor cells (MDA-MB-435 and SW480) is not obvious.

“Its antiproliferative activity against a variety of wild-type p53 inactivated tumor cells is 1–2 μM (including HCT116, RKO and SJSA-1), but its activity against mutant p53 tumor cells (MDA-MB-435 and SW480) is not obvious [22].”

• cites [22] Crane EK, Kwan SY, Izaguirre DI, et al. Nutlin-3a: a potential therapeutic opportunity for TP53 wild-type ovarian carcinomas. PLoS ONE. 2015;10(8): e0135101. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

ATM-dependent phosphorylation of MDM2 allows overexpressed MDM2 to bind p53 mRNA and promote p53 translation.

“The ATM-dependent phosphorylation of MDM2 allows the overexpressed MDM2 to bind p53 mRNA and promote p53 translation [10].”

• cites [10] Chibaya L, Karim B, Zhang H, Jones SN. Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis. Proc Natl Acad Sci USA. 2021;118(4): e2003193118. sourceNot checked yet

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MDM2 can bind p53 through PPI to prevent its expression under stress and inactivate or weaken its transcriptional function.

“First, the MDM2 protein can bind to the p53 protein through PPI to prevent its expression under stress conditions and then inactivate or weaken its transcriptional function.”

• cites [11] Hock AK, Vousden KH. The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta. 2014;1843(1):137–49. sourceNot checked yet

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• cites [12] Bang S, Kaur S, Kurokawa M. Regulation of the p53 family proteins by the ubiquitin proteasomal pathway. Int J Mol Sci. 2019;21(1):261. sourceNot checked yet

  Not checked in the free run.

• cites [13] do Patrocinio AB, Rodrigues V, Guidi Magalhães L. P53: Stability from the Ubiquitin-Proteasome System and Specific 26S Proteasome Inhibitors. ACS Omega. 2022;7(5):3836–3843. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

RO6839921 is an inactive PEGylated prodrug of RG7388, designed to improve exposure variability and pharmacokinetic characteristics of RG7388; intravenous injection at a safe dose showed good anti-tumor activity in osteosarcoma and AML xenograft models.

“RO6839921 is an inactive PEGylated prodrug of RG7388, which was designed to improve the exposure variability and pharmacokinetic characteristics of RG7388. Intravenous injection of RO6839921 at a safe dose showed good anti-tumor activity in osteosarcoma and AML xenograft models [33].”

• cites [33] Higgins B, Tovar C, Glen K, et al. Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration (abstract A156). Mol Cancer Ther. 2014;14(12 Supplement 2): A156. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The p53 protein is inactivated or mutated in more than 50% of cancer cells.

“As one of the most important tumor suppressors, the p53 protein is inactivated or mutated in more than 50% of cancer cells.”

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RG7112 was modified by Roche based on the structure of Nutlins and was the first MDM2 inhibitor introduced into clinical trials.

“RG7112 was modified by Roche based on the structure of Nutlins and was the first to be introduced into clinical trials (Fig. 4) [19].”

• cites [19] Vu B, Wovkulich P, Pizzolato G, et al. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett. 2013;4(5):466–9. sourceNot checked yet

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RG7388 binding activity to MDM2 reached 6 nM, antiproliferative activity against various tumor cells with high expression of wild-type p53 was approximately 300 nM, selectivity over p53 mutant tumor cells was greater than 100 times, oral bioavailability in mice reached 80%, half-life was 1.6 h, and metabolic stability was better than Compounds 1 and 2.

“The binding activity of RG7388 to MDM2 reached 6 nM, and the antiproliferative activity against various tumor cells with high expression of wild-type p53 was approximately 300 nM. The selectivity over p53 mutant tumor cells was greater than 100 times. The oral bioavailability in mice reached 80%, half-life was 1.6 h, and the metabolic stability was better than those of Compounds 1 and 2.”

• cites [29] Ding Q, Zhang Z, Liu JJ, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013;56(14):5979–83. sourceNot checked yet

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At 200 mg/kg, twice a day, 20 days after oral administration of Nutlin-3a, the tumor growth inhibition rate reached 90%, with no obvious side effects.

“At 200 mg/kg, twice a day, 20 days after oral administration of Nutlin-3a, the tumor growth inhibition rate reached 90%, with no obvious side effects [20].”

• cites [20] Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303(5659):844–8. sourceNot checked yet

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Phase I clinical trials for patients with advanced solid tumors demonstrated that SAR405838 had good safety and pharmacokinetics, but was not able to be administered at the planned weekly maximum tolerance dose.

“Phase I clinical trials for patients with advanced solid tumors demonstrated that SAR405838 had good safety and pharmacokinetics, but was not able to be administered at the planned weekly maximum tolerance dose [42].”

• cites [42] de Jonge M, de Weger VA, Dickson MA, et al. A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours. Eur J Cancer. 2017;76:144–51. sourceNot checked yet

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RG7112 has growth inhibition and killing effects on SJSA-1 osteosarcoma cells with high expression of MDM2 protein in vitro, and induces dose-dependent cell cycle arrest in HCT116 and SJSA1 cells at G1 and G2/M phases.

“RG7112 has been demonstrated to have growth inhibition and killing effects on SJSA-1 osteosarcoma cells with a high expression of MDM2 protein in vitro. Dose-dependent cell cycle arrest was induced in HCT116 and SJSA1 cells at the G1 and G2/M phases [23].”

• cites [23] Tovar C, Graves B, Packman K, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 2013;73(8):2587–97. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The MDM2 gene locates on chromosome 12q13~14, has a full length of 2372 kb, includes 12 exons, and encodes a protein containing 498 amino acids.

“The MDM2 gene locates on the long arm 13 ~ 14 of chromosome 12 (12q13 ~ 14), with a full length of 2372 kb, including 12 exons, encoding a protein containing 498 amino acids (Fig. 2).”

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MI-77301 (SAR405838) binding activity with MDM2 reached 0.88 nM, with high selectivity and high specificity over other proteins.

“MI-77301 (SAR405838) was obtained by simply replacing the groups exposed to the solvent region of MI-888, and its binding activity with MDM2 reached 0.88 nM, with a high selectivity and high specificity over other proteins [40].”

• cites [40] Wang S, Sun W, Zhao Y, et al. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 2014;74(20):5855–65. sourceNot checked yet

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In liposarcoma patients treated with RG7112, p53 and downstream p21 levels were significantly increased, one case of PR and 14 cases of SD were found in 17 assessable patients; at least one adverse reaction occurred in all patients, including 12 serious adverse reactions, including neutropenia and thrombocytopenia in eight patients.

“Although the levels of p53 and downstream p21 in patients with liposarcoma treated with this drug were significantly increased, one case of PR and 14 cases of SD were found in 17 assessable patients. However, at least one adverse reaction occurred in all patients, including 12 serious adverse reactions, including neutropenia and thrombocytopenia in eight patients [25].”

• cites [25] Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012;13(11):1133–40. sourceNot checked yet

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MI-63 binding activity with MDM2 was 3 nM, 2000 times higher than p53 peptide (residues 13-29); MI-63 selectively blocked p53-MDM2 without affecting Bcl-2-Bid, its tumor inhibitory effect was wild-type p53-dependent, and it induced apoptosis of tumor cells in chronic lymphocytic leukemia.

“The binding activity of MI-63 with MDM2 was 3 nM, which was 2000 times higher than that of the p53 peptide (residues 13–29). MI-63 had high stereospecificity and selectively blocked the interaction of p53–MDM2 without affecting the interaction of Bcl-2-Bid. Its inhibitory effect on tumor was wild-type p53-dependent, and its toxicity to p53 knockout cells and normal cells was small. In addition, MI”

• cites [37] Saddler C, Ouillette P, Kujawski L, et al. Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia. Blood. 2008;111(3):1584–93. sourceNot checked yet

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In the SJSA-1 osteosarcoma model, AMG232 has obvious anti-tumor activity and significantly promotes tumor regression without obvious toxicity or side effects.

“In the SJSA-1 osteosarcoma model, its anti-tumor activity was obvious, and it could significantly promote tumor regression without obvious toxicity or side effects [54, 55].”

• cites [54] Rew Y, Sun D. Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014;57(15):6332–41. sourceNot checked yet

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• cites [55] Sun D, Li Z, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014;57(4):1454–72. sourceNot checked yet

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A phase I clinical trial demonstrated that NVP-CGM097 can control solid tumor progression by activating the p53 pathway and has acceptable pharmacokinetic parameters and safety.

“A phase I clinical trial demonstrated that NVP-CGM097 can control solid tumor progression by activating the p53 pathway and has acceptable pharmacokinetic parameters and safety [74].”

• cites [74] Bauer S, Demetri G, Jeay S, et al. A phase I, open-label, multi-center, dose escalation study of oral NVP-CGM097, a p53/HDM2-protein-protein interaction inhibitor, in adult patients with selected advanced solid tumors. Ann Oncol. 2016;27:116. sourceNot checked yet

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p53 mutant BON1 and NCI-H727 cells were resistant to NVP-CGM097, but when combined with 5-fluorouracil, it played a potential role in treating neuroendocrine tumors by increasing expression of p53 and p21.

“The p53 mutant BON1 and NCI-H727 cells were resistant to NVP-CGM097, but when it was combined with 5-fluorouracil, it played a potential role in treating neuroendocrine tumors by increasing the expression of p53 and p21 [72].”

• cites [72] Reuther C, Heinzle V, Nölting S, et al. The HDM2 (MDM2) inhibitor NVP-CGM097 inhibits tumor cell proliferation and shows additive effects with 5-fluorouracil on the p53–p21-Rb-E2F1 cascade in the p53wild type neuroendocrine tumor cell line GOT1. Neuroendocrinology. 2018;106(1):1–19. sourceNot checked yet

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Compound 12 has improved metabolic stability, reduced intrinsic clearance rate, and improved affinity for MDM2 protein and cell activity.

“Its metabolic stability was further improved, its intrinsic clearance rate was reduced, and its affinity for MDM2 protein and cell activity was also improved [53].”

• cites [53] Rew Y, Sun D, Gonzalez-Lopez De Turiso F, et al. Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem. 2012;55(11):4936–4954. sourceNot checked yet

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Structure-activity relationship studies showed that the butoxy and chlorobenzene parts of Compound 17 had small structural modification potential, and groups introduced in the Phe19 cavity can enhance binding, with its 4-pyridine ring surrounded by Tyr-67, Met-62 and Gln-72 amino acids of MDM2 significantly enhancing binding to MDM2.

“Structure–activity relationship studies showed that these two parts had small structural modification potential. In the Phe19 cavity, groups can be introduced to enhance its binding to the cavity, and its 4-pyridine ring is surrounded by Tyr-67, Met-62 and Gln-72 amino acids of MDM2, which can significantly enhance its binding to MDM2 [67].”

• cites [67] Gessier F, Kallen J, Jacoby E, et al. Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg Med Chem Lett. 2015;25(17):3621–5. sourceNot checked yet

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Phase I trials showed that APG-115 had good tolerance, controllable adverse reactions and good anti-tumor activity.

“Phase I trials showed that APG-115 had good tolerance, controllable adverse reactions and good anti-tumor activity [48] and demonstrated the potential to mediate drug resistance in immunotherapy [49, 50].”

• cites [48] Rasco DW, Lakhani NJ, Li Y, et al. A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors. Cancer Res. 2019;37:3126.Not checked yet

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• cites [49] Tolcher AW, Fang DD, Li Y, et al. A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors. Ann Onco. 2019;30: i2. sourceNot checked yet

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• cites [50] Tolcher AW, Reeves JA, McKean M, et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (IO) drugs. Cancer Res. 2021;39:2506.Not checked yet

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APG-115 has activity greater than 10 times that of SAR405838 and overcomes pharmaceutical defects of slow isomerization reaction and poor solubility in a neutral environment in SAR405838.

“APG-115 has obvious activity and drug administration advantages and overcomes the pharmaceutical defects of a slow isomerization reaction and poor solubility in a neutral environment in the early clinical compound SAR405838, with an activity greater than 10 times that of SAR405838.”

May combine two claims.

AMG232 morpholinone scaffold could simulate the three key amino acid residues of p53 binding to MDM2 (IC50 = 5.4 μM), and introduction of a benzyl group at C2 enhanced activity.

“After preliminary evaluation, it was determined that the morpholinone scaffold could well simulate the three key amino acid residues (IC50 = 5.4 μM) of p53 binding to MDM2, and the introduction of a benzyl group at the C2 position enhanced the activity of Compound 5.”

• cites [52] Gonzalez-Lopez de Turiso F, Sun D, Rew Y, et al. Rational design and binding mode duality of MDM2-p53 inhibitors. J Med Chem. 2013;56(10):4053–4070. sourceNot checked yet

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When NVP-CGM097 binds to MDM2 protein, the dihydroisoquinolinone scaffold is not completely planar, resulting in conformational energy loss, which can be overcome by van der Waals forces or hydrogen bonding interactions with binding sites.

“When NVP-CGM097 binds to the MDM2 protein, the scaffold of dihydroisoquinolinone is not completely planar, and therefore, the combination of NVP-CGM097 and the MDM2 protein results in a conformational energy loss, which can be overcome by van der Waals forces or hydrogen bonding interactions with binding sites.”

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Substitution of the ester site for hydroxymethyl in the AMG232 series improved activity to 1.1 nM, resulted in a low clearance rate (CL = 0.03 L/H/Kg), higher target selectivity than Compound 11, and reduced inhibition rates of CYP450, CYP3A4 and hPXR.

“The substitution of the ester site for hydroxymethyl improved the activity to 1.1 nM, resulted in a low clearance rate (CL = 0.03 L/H/Kg) with higher target selectivity than Compound 11, and reduced the inhibition rates of CYP450, CYP3A4 and hPXR.”

• cites [52] Gonzalez-Lopez de Turiso F, Sun D, Rew Y, et al. Rational design and binding mode duality of MDM2-p53 inhibitors. J Med Chem. 2013;56(10):4053–4070. sourceNot checked yet

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NVP-CGM097 can reverse multidrug resistance of tumor caused by ABCB1 by blocking drug efflux mediated by ABCB1 and improving therapeutic effect of chemotherapy.

“NVP-CGM097 can also reverse the multidrug resistance of tumor caused by ABCB1 (ATP binding cassette subfamily B member 1) by blocking the drug efflux mediated by ABCB1 and improving the therapeutic effect of chemotherapy [73].”

• cites [73] Zhang M, Chen XY, Dong XD, et al. NVP-CGM097, an HDM2 inhibitor, antagonizes ATP-binding cassette subfamily B member 1-mediated drug resistance. Front Oncol. 2020;10:1219. sourceNot checked yet

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In a Phase I trial on AML patients, AMG232 had serious gastrointestinal adverse reactions at high doses but had objective pharmacokinetic parameters, targeting and clinical activity.

“A Phase I trial on AML patients showed that although AMG232 had serious gastrointestinal adverse reactions at high doses, it had objective pharmacokinetic parameters, targeting and clinical activity [66].”

• cites [66] Erba HP, Becker PS, Shami PJ, et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv. 2019;3(13):1939–49. sourceNot checked yet

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When the pyridine ring was substituted with piperidine and other rings, affinity to MDM2 protein and cell activity were significantly enhanced, and it showed good ADME parameters in vitro.

“when the pyridine ring was substituted with piperidine and other rings, its affinity to MDM2 protein and cell activity were significantly enhanced, and at the same time, it showed good ADME parameters in vitro.”

May combine two claims.

HDM201 could selectively induce cell cycle arrest and apoptosis of p53 wild-type tumors and had dose-dependent PKPD parameters to inhibit SJSA-1 in vivo growth.

“HDM201 could selectively induce cell cycle arrest and apoptosis of p53 wild-type tumors and had dose-dependent PKPD parameters to inhibit SJSA-1 in vivo growth [77–79].”

• cites [77] Jeay S, Chène P, Ferretti S, et al. NVP-HDM201: cellular and in vivo profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. Cancer Res. 2016;76:1225. sourceNot checked yet

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• cites [78] Ferretti S, Rebmann R, Berger M, et al. Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. Cancer Res. 2016;76:1224. sourceNot checked yet

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• cites [79] Meille C, Guerreiro N, Jullion A, et al. Abstract CT154: Optimization of the dose and schedule of an HDM2 inhibitor NVP-HDM201 in a first-in-human Phase I study using a mechanism-based PK/PD model. Cancer Res. 2017;77:CT154. sourceNot checked yet

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AMG232 has low inhibitory activities against CYP, CYP3A4 and PXR.

“low inhibitory activities against CYP, CYP3A4 and PXR”

• cites [54] Rew Y, Sun D. Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014;57(15):6332–41. sourceNot checked yet

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May combine two claims.

Compound 18 had typical PK parameters of tertiary amine compounds, with wide distribution in vivo and long half-life, but low in vivo clearance rate.

“Compound 18 had typical PK parameters of tertiary amine compounds, with a wide distribution in vivo and long half-life. However, its in vivo clearance rate was low.”

May combine two claims.

The cocrystal structure of Compound 17 with MDM2 protein showed binding modes different from existing MDM2 inhibitors, with butoxy and chlorobenzene occupying Leu26 and Trp23 cavities, respectively.

“The cocrystal structure of Compound 17 with MDM2 protein showed that it had binding modes that were different from the existing MDM2 inhibitors. Butoxy and chlorobenzene occupied Leu26 and Trp23 cavities, respectively.”

• cites [67] Gessier F, Kallen J, Jacoby E, et al. Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg Med Chem Lett. 2015;25(17):3621–5. sourceNot checked yet

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May combine two claims.

Nutlin-3a had little difference in affinity to MDM2 protein in different species, while NVP-CGM097 had great difference; the binding ability of NVP-CGM097 to human MDM2 was 16 times higher than that to dog MDM2.

“When comparing the binding ability of NVP-CGM097 and Nutlin-3a to MDM2 protein in different species, Nutlin-3a had little difference in affinity to MDM2 protein in different species, while NVP-CGM097 had great difference. The binding ability of NVP-CGM097 to human MDM2 was 16 times higher than that to dog MDM2”

May combine two claims.

The imidazole ring reduced the lipophilicity of the compound, and an intermediate scaffold prepared with pyrrolidone and imidazole rings resulted in Compound 21.

“It was found that the imidazole ring reduced the lipophilicity of the compound, and therefore, an intermediate scaffold was prepared with pyrrolidone and imidazole rings, which resulted in Compound 21.”

May combine two claims.

Single-dose oral administration of APG-115 effectively activated p53 protein in SJSA-1 xenograft tumor in mice and caused complete and permanent regression of the tumor, as well as in RS4;11 AML model.

“Single-dose oral administration of APG-115 could effectively activate the p53 protein in SJSA-1 xenograft tumor in mice and cause complete and permanent regression of the tumor, as well as in RS4;11 AML model.”

• cites [46] Aguilar A, Lu J, Liu L, et al. Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. J Med Chem. 2017;60(7):2819–2839. sourceNot checked yet

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May combine two claims.

AMG232, MEK inhibitors and DNA damage-induced chemotherapy have synergistic tumor-killing effects, and combination therapy can significantly increase anti-AML effects in vivo.

“AMG232, MEK inhibitors and DNA damage-induced chemotherapy have synergistic tumor-killing effects, and combination therapy can significantly increase anti-AML effects in vivo [61].”

• cites [61] Canon JR, Osgood T, Saiki AY, et al. The MDM2 inhibitor AMG 232 causes tumor regression and potentiates the anti-tumor activity of MEK inhibition and DNA-damaging cytotoxic agents in preclinical models of acute myeloid leukemia. Cancer Res. 2016;76:3761. sourceNot checked yet

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May combine two claims.

APG-115 showed a strong binding ability with MDM2 protein (Ki < 1 nM), activated p53 protein in a variety of tumor cells, inhibited cell proliferation at nM concentrations, and had enhanced selectivity over p53 knockout tumor cells.

“Compound 3 was used as the lead compound for a systematic structure–activity relationship study to obtain APG-115 (Fig. 10), which showed a strong binding ability with MDM2 protein (Ki < 1 nM) [46]. It could activate p53 protein in a variety of tumor cells and inhibit cell proliferation at nM concentrations, with an enhancement in its selectivity over p53 knockout tumor cells.”

• cites [46] Aguilar A, Lu J, Liu L, et al. Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. J Med Chem. 2017;60(7):2819–2839. sourceNot checked yet

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May combine two claims.

Compound 17 has binding activity with MDM2 protein of 8 nM (TR-FRET) and anti-tumor activity in SJSA-1 cells at the μM level.

“After preliminary structural optimization, Compound 17 was obtained, and its binding activity with MDM2 protein was 8 nM (TR-FRET). The anti-tumor activity in SJSA-1 cells was at the μM level.”

• cites [67] Gessier F, Kallen J, Jacoby E, et al. Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg Med Chem Lett. 2015;25(17):3621–5. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a phase I trial, AMG232 showed good safety and pharmacokinetic parameters in patients with p53 WT advanced solid tumor or multiple myeloma and could control disease progression.

“In a phase I trial, AMG232 showed good safety and pharmacokinetic parameters in patients with p53 WT advanced solid tumor or multiple myeloma and could control the progression of the disease [64].”

• cites [64] Gluck WL, Gounder MM, Frank R, et al. Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma. Invest New Drug. 2020;38(3):831–43. sourceNot checked yet

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May combine two claims.

Derivatization of the terminal dimethylamino group with imidazolidinone or piperazinone produced the strongest activity with good PK parameters, reduced in vivo distribution and half-life, and retained an intermediate in vivo clearance rate.

“When this group was derivatized with imidazolidinone or piperazinone, the activity of the target compound was the strongest with good PK parameters and reduced in vivo distribution and half-life, and retained an intermediate in vivo clearance rate.”

May combine two claims.

Compound 22 was effective in the SJSA-1 tumor model without affecting animal weight, and compared with NVP-CGM097, had more potential as a clinical candidate.

“Finally, Compound 22 was obtained, which was effective in the SJSA-1 tumor model without affecting animal weight, compared with NVP-CGM097, which had more potential as the clinical candidate [76].”

• cites [76] Vaupel A, Holzer P, Ferretti S, et al. In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor. Bioorg Med Chem Lett. 2018;28(20):3404–8. sourceNot checked yet

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May combine two claims.

Combined application of AMG232 and anti-PD-1 antibodies can enhance the killing effect of T cells on tumor cells and has the potential to overcome drug resistance of immunotherapy.

“the combined application of AMG232 and anti-PD-1 antibodies can enhance the killing effect of T cells on tumor cells and had the potential to overcome the drug resistance of immunotherapy [63].”

• cites [63] Sahin I, Zhang S, Navaraj A, et al. AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing. Cell Death Discov. 2020;6:57. sourceNot checked yet

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May combine two claims.

In a phase I clinical trial on metastatic cutaneous melanoma, AMG232 combined with trametinib or dabrafenib had a tolerated dose, safety and pharmacokinetic parameters, and early anti-tumor activity.

“A phase I clinical trial on metastatic cutaneous melanoma demonstrated that AMG232 combined with trametinib or dabrafenib had a tolerated dose, safety and pharmacokinetic parameters, and early anti-tumor activity [65].”

• cites [65] Moschos SJ, Sandhu SK, Lewis KD, et al. Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (Pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM). Cancer Res. 2017;35:2575.Not checked yet

  Not checked in the free run.

May combine two claims.

Compared with compound 18, the derivatized compound had better absorption efficiency and oral bioavailability.

“Compared with compound 18, it had better absorption efficiency and oral bioavailability.”

May combine two claims.

NVP-CGM097 had synergistic anti-BRAF mutation melanoma cell proliferation with RAF kinase inhibitor and synergistic anti-ALK mutation neuroblastoma with ALK inhibitor and prolonged survival.

“It had the effect of synergistic anti-BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutation melanoma cell proliferation with RAF kinase inhibitor [70], and synergistic anti-ALK (anaplastic lymphoma kinase) mutation neuroblastoma with ALK inhibitor and prolonged survival [71].”

• cites [70] Wang HQ, Zubrowski M, Emerson E, et al. The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma. Cancer Res. 2014;74:5466. sourceNot checked yet

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• cites [71] Wang HQ, Battalagine L, Liang J, et al. The Mdm2 inhibitor NVP-CGM097 enhances the anti-tumor activity of NVP-LDK378 in ALK mutant neuroblastoma models. Cancer Res. 2014;74:2929. sourceNot checked yet

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May combine two claims.

Compound 12 occupies the three key active cavities of MDM2, occupies the Gly58 cavity, and interacts electrostatically with His96.

“As expected, the compound could occupy the three key active cavities, occupy the Gly58 cavity and interact electrostatically effect with His96.”

• cites [53] Rew Y, Sun D, Gonzalez-Lopez De Turiso F, et al. Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem. 2012;55(11):4936–4954. sourceNot checked yet

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May combine two claims.

NVP-CGM097, obtained by ammonia methylation of piperazinone to enhance permeability, showed good cell activity, metabolic stability and PK parameters.

“Finally, NVP-CGM097 was obtained by ammonia methylation of piperazinone to enhance its permeability, which showed good cell activity, metabolic stability and PK parameters [68].”

• cites [68] Holzer P, Masuya K, Furet P, et al. Discovery of a dihydroisoquinolinone derivative (NVP-CGM097): a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors. J Med Chem. 2015;58(16):6348–58. sourceNot checked yet

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May combine two claims.

Compound 20 has improved binding ability to 0.13 nM and cell activity to 90 nM.

“which led to the discovery of Compound 20 with further improved binding ability to 0.13 nM and cell activity to 90 nM [75].”

• cites [75] Furet P, Masuya K, Kallen J, et al. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg Med Chem Lett. 2016;26(19):4837–41. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A clinical study of RG7388 showed no obvious p53 activation and serious dose-dependent side effects.

“A clinical study of RG7388 also showed similar phenomenon, with no obvious p53 activation and serious dose-dependent side effects [88].”

• cites [88] Yee K, Martinelli G, Vey N, et al. Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (Pts). Blood. 2014;124:116. sourceNot checked yet

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May combine two claims.

The safety and clinical efficacy of HDM201 against liposarcoma in combination with LEE011 (a CDK4/6 inhibitor) were confirmed.

“The safety and clinical efficacy of HDM201 against liposarcoma in combination with LEE011 (a CDK4/6 inhibitor) were also confirmed [86].”

• cites [86] Razak AA, Bauer S, Blay JY, et al. Abstract CT009: Results of a dose-and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma. Cancer Res. 2018;78(13 Supplement): CT009. sourceNot checked yet

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May combine two claims.

ALRN-6924 was well tolerated, and the most common adverse side effect was gastrointestinal.

“ALRN-6924 was well tolerated, and the most common adverse side effect was gastrointestinal [115].”

• cites [115] Meric-Bernstam F, Saleh M N, Infante J R, et al. Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX-and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas. J Clin Oncol. 2017;35(15_suppl): 2505. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The PKPD model of HDM201 demonstrated that anti-tumor activity of HDM201 was not schedule dependent but related to cumulative dose.

“The PKPD model of HDM201 also demonstrated that the anti-tumor activity of HDM201 was not scheduled dependent, but was related to cumulative dose [81]”

• cites [81] Guerreiro N, Jullion A, Ferretti S, Fabre C, Meille C. Translational modeling of anticancer efficacy to predict clinical outcomes in a first-in-human phase 1 study of MDM2 inhibitor HDM201. AAPS J. 2021;23(2):28. sourceNot checked yet

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May combine two claims.

Development of MDM2/MDMX dual-target inhibitors may solve the problems existing in clinical research of MDM2 inhibitors and has great practical significance for treatment of related tumors.

“It seems that the development of MDM2/MDMX dual-target inhibitors may solve the problems existing in the clinical research of the above MDM2 inhibitors and has great practical significance for the treatment of related tumors [97, 108, 109].”

• cites [97] Michaelis M, Rothweiler F, Barth S, et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis. 2011;2(12): e243. sourceNot checked yet

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• cites [108] Graves B, Thompson T, Xia M, et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci USA. 2012;109(29):11788–93. sourceNot checked yet

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• cites [109] Wu D, Prives C. Relevance of the p53-MDM2 axis to aging. Cell Death Differ. 2018;25(1):169–79. sourceNot checked yet

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• AssumptionRests on an assumption: The binding cavity of MDMX is more flexible than that of MDM2.

May combine two claims.

Inhibition of MDM2 alone cannot completely release and activate p53 protein, which can induce overexpression of MDMX, thereby reducing the effect of MDM2 inhibitors and promoting drug resistance.

“Inhibition of MDM2 alone cannot completely release and activate p53 protein [25, 105], which can induce the overexpression of MDMX, thereby reducing the effect of MDM2 inhibitors and promoting drug resistance [106].”

• cites [25] Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012;13(11):1133–40. sourceNot checked yet

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• cites [105] Siu LL, Italiano A, Miller WH, et al. Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors. J Clin Oncol. 2014;32(15):2535–2535. sourceNot checked yet

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• cites [106] Watters JW, Dickson MA, Schwartz GK, et al. TP53 mutations emerge in circulating cell-free DNA obtained from patients undergoing treatment with the HDM2 antagonist SAR405838. J Clin Oncol. 2015;33(15):2515–2515. sourceNot checked yet

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May combine two claims.

Although missense mutations in MDM2 are rare, multiple isoforms of MDM2 protein generated by alternative promoters and alternative proteins have been observed, and the change in sequence may disrupt the N-terminal p53-binding domain to reduce efficacy of MDM2 inhibitors and promote tumor progression.

“although missense mutations in MDM2 are rare, multiple isoforms of MDM2 protein generated by alternative promoters and alternative proteins have been observed, and the change in the sequence may disrupt the N-terminal p53-binding domain to reduce the efficacy of MDM2 inhibitors and promote tumor progression [100–103].”

• cites [100] Bartel F, Harris LC, Würl P, et al. MDM2 and its splice variant messenger RNAs: expression in tumors and down-regulation using antisense Oligonucleotides11NIH grants CA92401 and CA21765, American Lebanese Syrian Associated Charities (LCH), Deutsche Krebshilfe eV grant 2130-Ta2, Land Sachsen-Anhalt grant 3347A/0021B, and GSGT eV (FB and HT). Mol Cancer Res. 2004;2(1):29–35. sourceNot checked yet

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• cites [101] Okoro DR, Rosso M, Bargonetti J. Splicing up mdm2 for cancer proteome diversity. Genes Cancer. 2012;3(3–4):311–9. sourceNot checked yet

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• cites [102] Lim CC, Chan SK, Lim YY, et al. Development and structural characterisation of human scFv targeting MDM2 spliced variant MDM215kDa. Mol Immunol. 2021;135:191–203. sourceNot checked yet

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• cites [103] Comiskey DF Jr, Montes M, Khurshid S, Singh RK, Chandler DS. SRSF2 Regulation of MDM2 reveals splicing as a therapeutic vulnerability of the p53 pathway. Mol Cancer Res. 2020;18(2):194–203. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

RG7112 was an outstanding candidate in preclinical research and demonstrated strong anti-tumor proliferation activity against various tumor cells, but its efficacy in clinical research was not obvious, almost all tumor patients had no obvious tumor response, and nearly half of the patients had multiple serious adverse reactions such as neutropenia and thrombocytopenia.

“RG7112 was an outstanding candidate in preclinical research and demonstrated strong anti-tumor proliferation activity against various tumor cells. However, its efficacy in clinical research was not obvious, almost all tumor patients had no obvious tumor response, and nearly half of the patients had multiple serious adverse reactions (such as neutropenia and thrombocytopenia) [26].”

• cites [26] Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22(4):868–76. sourceNot checked yet

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May combine two claims.

Application of MDM2/MDMX dual-target inhibitors can activate higher levels of p53 protein than single-target inhibitors with better anticancer efficacy, indicating simultaneous inhibition of MDM2 and MDMX proteins can effectively regulate expression of p53 protein.

“Studies have shown that the application of MDM2/MDMX dual-target inhibitors can activate higher levels of p53 protein than single-target inhibitors with a better anticancer efficacy, indicating that the simultaneous inhibition of MDM2 and MDMX proteins can effectively regulate the expression of p53 protein.”

May combine two claims.

MDM2 inhibitors may promote the emergence of p53 mutations and lead to genomic instability through a p53-independent mechanism, resulting in acquired resistance against MDM2 inhibitors.

“MDM2 inhibitors may promote the emergence of p53 mutations and lead to genomic instability through a p53-independent mechanism, resulting in acquired resistance against MDM2 inhibitors [97–99].”

• cites [97] Michaelis M, Rothweiler F, Barth S, et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis. 2011;2(12): e243. sourceNot checked yet

  Not checked in the free run.

• cites [98] Melo AN, Eischen CM. Protecting the genome from mdm2 and mdmx. Genes Cancer. 2012;3(3–4):283–90. sourceNot checked yet

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• cites [99] Haronikova L, Bonczek O, Zatloukalova P, et al. Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: Can we overcome them? Cell Mol Biol Lett. 2021;26(1):53. sourceNot checked yet

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May combine two claims.

Phase I clinical results showed that HDM201 had good pharmacokinetic parameters and safety, with no significant difference between its safety and tumor type and treatment plan, and it was prone to thrombocytopenia.

“Phase I clinical results showed that HDM201 had good pharmacokinetic parameters and safety, and there was no significant difference between its safety and tumor type and treatment plan, and it was prone to thrombocytopenia [83].”

• cites [83] Stein EM, DeAngelo DJ, Chromik J, et al. Results from a first-in-human phase I study of siremadlin (HDM201) in patients with advanced wild-type TP53 solid tumors and acute leukemia. Clin Cancer Res. 2022;28(5):870–81. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ALRN-6924 is being evaluated as a monotherapy and in combination with cytarabine in patients with hematological malignancies (NCT02909972) and has entered a Phase I/II clinical trial in patients with advanced solid tumors or with preserved wild-type p53 lymphoma (NCT02264613).

“Clinically, ALRN-6924 is being evaluated as a monotherapy and in combination with cytarabine in patients with hematological malignancies (NCT02909972) and has entered a Phase I/II clinical trial in patients with advanced solid tumors or with preserved wild-type p53 lymphoma (NCT02264613).”

May combine two claims.

The MDMX inhibitor SJ-172550 is extremely unstable, easily deteriorates in solution, and the basis of its specific role is not clear.

“the MDMX inhibitor SJ-172550 was reported to be extremely unstable [110]. It easily deteriorates in solution, and the basis of its specific role is not clear.”

• cites [110] Stefaniak J, Lewis AM, Conole D, et al. Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors. ACS Chem Biol. 2018;13(10):2849–54. sourceNot checked yet

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May combine two claims.

Cell-penetrating stapled α-helical peptides are another promising class of MDM2/MDMX inhibitors, with ATSP-7041 and its analog ALRN-6924 being the most promising.

“In addition to small-molecule inhibitors, another promising class of MDM2/MDMX inhibitors is cell-penetrating stapled α-helical peptides. The most promising is ATSP-7041 and its analog ALRN-6924 [114, 115].”

• cites [114] Chang YS, Graves B, Guerlavais V, et al. Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA. 2013;110(36):E3445–54. sourceNot checked yet

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• cites [115] Meric-Bernstam F, Saleh M N, Infante J R, et al. Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX-and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas. J Clin Oncol. 2017;35(15_suppl): 2505. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A biological classifier based on genome-wide association has the potential to discriminate response to MDM2-inhibitor therapy.

“Although the biological classifier based on the genome-wide association has the potential to discriminate response to MDM2-inhibitor therapy [104]”

• cites [104] Zhong H, Chen G, Jukofsky L, et al. MDM2 antagonist clinical response association with a gene expression signature in acute myeloid leukaemia. Br J Haematol. 2015;171(3):432–5. sourceNot checked yet

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May combine two claims.

The phase Ib trial with AML patients showed that AML patients had good tolerance and therapeutic response to HDM201 combined with Bcl-2 inhibitors.

“The phase Ib trial with AML patients showed that AML patients had a good tolerance and therapeutic response to HDM201 combined with Bcl-2 inhibitors [85].”

• cites [85] Wei AH, Breccia M, Ooi M, et al. Preliminary results from a phase Ib study exploring MDM2 inhibitor siremadlin (HDM201) in combination with B-cell lymphoma-2 (BCL-2) Inhibitor venetoclax in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS). Blood. 2021;138:1283. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The wild-type p53-PUMA pathway has the potential to drive the metabolic switch of cancer cells, and wild-type p53 is required for the maintenance of cancer cell growth and glycolysis in several cancers.

“The wild-type p53-PUMA pathway was found to have the potential to drive the metabolic switch of cancer cells, and wild-type p53 is required for the maintenance of cancer cell growth and glycolysis in several cancers [93]”

• cites [93] Kim J, Yu L, Chen W, et al. Wild-type p53 promotes cancer metabolic switch by inducing PUMA-dependent suppression of oxidative phosphorylation. Cancer Cell. 2019;35(2):191-203.e8. sourceNot checked yet

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May combine two claims.

Only indole-acetylureas and pseudopeptides have been reported to have dual protein inhibitory effects on MDM2 and MDMX, with few structural types, unclear mechanisms of action, and no further studies.

“Only indole-acetylureas and pseudopeptides have been reported to have dual protein inhibitory effects onMDM2 and MDMX [111–113], with few structural types, unclear mechanisms of action, and no further studies.”

• cites [111] Giustiniano M, Daniele S, Pelliccia S, et al. Computer-aided identification and lead optimization of dual murine double minute 2 and 4 binders: structure-activity relationship studies and pharmacological activity. J Med Chem. 2017;60(19):8115–30. sourceNot checked yet

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• cites [112] Twarda-Clapa A, Krzanik S, Kubica K, et al. 1,4,5-Trisubstituted imidazole-based p53-MDM2/MDMX antagonists with aliphatic linkers for conjugation with biological carriers. J Med Chem. 2017;60(10):4234–44. sourceNot checked yet

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• cites [113] Merlino F, Daniele S, La Pietra V, et al. Simultaneous targeting of RGD-integrins and dual murine double minute proteins in glioblastoma multiforme. J Med Chem. 2018;61(11):4791–809. sourceNot checked yet

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May combine two claims.

In the clinical study of AMG232, ccfDNA mutation was found; after continuous administration, mutation frequency gradually increased, and a variety of p53 mutations occurred, resulting in severe drug resistance.

“the mutation of ccfDNA (circulating cell-free DNA) was also found in the clinical study of AMG232. After continuous administration of medication, the mutation frequency gradually increased, and a variety of p53 mutations also occurred, resulting in severe drug resistance [65].”

• cites [65] Moschos SJ, Sandhu SK, Lewis KD, et al. Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (Pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM). Cancer Res. 2017;35:2575.Not checked yet

  Not checked in the free run.

May combine two claims.

In some tumors, such as liver cancer and breast cancer, inactivation of p53 protein is mainly related to overexpression of MDMX, and therefore, MDM2 inhibitors have shown little effect on such tumors.

“in some tumors, such as liver cancer and breast cancer, the inactivation of p53 protein is mainly related to the overexpression of MDMX, and therefore, MDM2 inhibitors have shown little effect on such tumors [107].”

• cites [107] Lam S, Lodder K, Teunisse AF, Rabelink MJ, Schutte M, Jochemsen AG. Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene. 2010;29(16):2415–26. sourceNot checked yet

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May combine two claims.

He et al. discovered an oral dual inhibitor of MDM2 and HDAC, which had excellent anti-tumor effect in xenograft models.

“He et al. discovered an oral dual inhibitor of MDM2 and HDAC (histone deacetylase), which had excellent anti-tumor effect in xenograft models [118].”

• cites [118] He S, Dong G, Wu S, et al. Small molecules simultaneously inhibiting p53-murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs): discovery of novel multitargeting antitumor agents. J Med Chem. 2018;61(16):7245–60. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Targeting MDM2/TPSO, MDM2/PKC, MDM2/NF-kB, MDM2/Bcl-2 and MDM2/NFAT1 had good anti-tumor activity and had the potential to reduce adverse reactions of MDM2 inhibitors.

“Targeting MDM2/TPSO (translocator protein) [119], MDM2/PKC (protein kinase C) [120], MDM2/NF-kB (nuclear factor-kappa B) [121], MDM2/Bcl-2 (B-cell lymphoma-2) [122] and MDM2/NFAT1 (nuclear factor of activated T-cells 1) [123] had good anti-tumor activity and had the potential to reduce the adverse reactions of MDM2 inhibitors.”

• cites [119] Daniele S, La Pietra V, Barresi E, et al. Lead optimization of 2-phenylindolylglyoxylyldipeptide murine double minute (MDM)2/translocator protein (TSPO) dual inhibitors for the treatment of gliomas. J Med Chem. 2016;59(10):4526–38. sourceNot checked yet

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• cites [120] Carita G, Frisch-Dit-Leitz E, Dahmani A, et al. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. Oncotarget. 2016;7(23):33542–56. sourceNot checked yet

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• cites [121] Shirai Y, Shiba H, Iwase R, et al. Dual inhibition of nuclear factor kappa-B and Mdm2 enhance the antitumor effect of radiation therapy for pancreatic cancer. Cancer Lett. 2016;370(2):177–84. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The specificity of MDM2-p53 protein interaction brings considerable difficulties to development of small-molecule inhibitors, resulting in only a handful candidates under clinical trials, and no marketed drugs targeting MDM2.

“the specificity of MDM2–p53 protein interaction brings considerable difficulties to the development of small-molecule inhibitors, resulting in only a handful candidates under clinical trials, and no marketed drugs targeting MDM2.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The multi-target strategy or targeted degradation strategy based on MDM2 has the potential to improve clinical defects of MDM2 inhibitors, but more evidence is needed to confirm its clinical application value.

“The multi-target strategy or targeted degradation strategy based on MDM2 has the potential to improve the clinical defects of MDM2 inhibitors, but more evidence is still needed to confirm its clinical application value.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

MDM2 inhibitors have the potential to be incorporated into cyclotherapy, since low-dose MDM2 inhibitors could arrest the cell cycle and prevent S-Phase and M-Phase drug damage to p53 proficient normal cells.

“MDM2 inhibitors have the potential to be incorporated into cyclotherapy, since low-dose MDM2 inhibitors could arrest the cell cycle and prevent S-Phase and M-Phase drug damage to p53 proficient normal cells.”

May combine two claims.

MX69 showed little effect on normal human hematopoietic function in vitro and was well tolerated in animal models.

“Importantly, it showed little effect on normal human hematopoietic function in vitro and was well tolerated in animal models [117]”

• cites [117] Gu L, Zhang H, Liu T, et al. Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell. 2016;30(4):623–36. sourceNot checked yet

  Not checked in the free run.