Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2–p53 Inhibitor in Clinical Development
Abstract
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
AMG-232 is more selective than RG-7112 for p53 wild cells.
“Studies have shown that AMG-232 is more selective than RG-7112 for p53 wild cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [387]
In vivo experiments showed that AMG-232 (10, 25, 75 mg kg−1, orally, once a day) activated the p53 pathway, effectively inhibited the growth of xenogeneic tumors in mice, blocked viral DNA synthesis, induced apoptosis, and caused dose-dependent tumor growth inhibition (ED50 = 16 mg kg−1).
“In vivo experiments showed that AMG-232 (10, 25, 75 mg kg−1, orally, once a day) activated the p53 pathway, effectively inhibited the growth of xenogeneic tumors in mice, blocked viral DNA synthesis, induced apoptosis, and caused dose-dependent tumor growth inhibition (ED50 = 16 mg kg−1).385–387”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [387]
In vitro experiments demonstrated that AMG-232 induced p53 signal transduction and inhibited tumor cell proliferation in three p53 wild tumor cell lines (SJSA-1, HCT116, and ACHN).
“In vitro experiments demonstrated that AMG-232 induced p53 signal transduction and inhibited tumor cell proliferation in three p53 wild tumor cell lines (SJSA-1, HCT116, and ACHN).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [387]
WB138 increases levels of both p53 and MDM2, consistent with previous reports on MDM2 inhibitors.
“WB138 increases the levels of both p53 and MDM2, which is consistent with the activity of previous reports on MDM2 inhibitors[28,32–36].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [36]
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].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [55]
Cites
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Reaching for high-hanging fruit in drug discovery at protein–protein interfaces
Wells, J. A., & McClendon, C. L. (2007) · Nature · doi:10.1038/nature06526 · Cited by 1,963 · see citing works
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949 · see citing works
Self-citationOncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · see citing works
Self-citationFundamental Properties of the CH···O Interaction: Is It a True Hydrogen Bond?
Gu, Y., Kar, T., & Scheiner, S. (1999) · Journal of the American Chemical Society · doi:10.1021/ja991795g · Cited by 1,008 · see citing works
Inhibiting the p53–MDM2 interaction: an important target for cancer therapy
Chène, P. (2003) · Nature Reviews Cancer · doi:10.1038/nrc991 · Cited by 765 · see citing works
Ding, K., Lu, Y., Nikolovska-Coleska, Z., Wang, G., Qiu, S., Shangary, S., Gao, W., Qin, D., Stuckey, J., Krajewski, K., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm051122a · Cited by 702 · see citing works
The genetics of the p53 pathway, apoptosis and cancer therapy
Vázquez, A., Bond, E. E., Levine, A. J., & Bond, G. L. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2656 · Cited by 674 · see citing works
Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development
Ding, Q., Zhang, Z., Liu, J.-J., Jiang, N., Zhang, J., Ross, T. M., Chu, X.-J., Bartkovitz, D., Podlaski, F., Janson, C., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400487c · Cited by 595 · see citing works
Self-citationDiscovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in Cells
Grasberger, B. L., Lu, T., Schubert, C., Parks, D. J., Carver, T. E., Koblish, H. K., Cummings, M. D., LaFrance, L. V., Milkiewicz, K. L., Calvo, R. R., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049137g · Cited by 433 · see citing works
Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development
Vu, B., Wovkulich, P., Pizzolato, G., Lovey, A., Ding, Q., Jiang, N., Liu, J.-J., Zhao, C., Glenn, K., Wen, Y., et al. (2013) · ACS Medicinal Chemistry Letters · doi:10.1021/ml4000657 · Cited by 395 · see citing works
Self-citationmdm-2 Inhibits the G1 Arrest and Apoptosis Functions of the p53 Tumor Suppressor Protein
Chen, J., Wu, X., Lin, J., & Levine, A. J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2445 · Cited by 350 · see citing works
Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction
Yu, S., Qin, D., Shangary, S., Chen, J., Wang, G., Ding, K., McEachern, D., Qiu, S., Nikolovska-Coleska, Z., Miller, R., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm901400z · Cited by 180 · see citing works
Parks, D. J., LaFrance, L. V., Calvo, R. R., Milkiewicz, K. L., Gupta, V., Lattanze, J., Ramachandren, K., Carver, T. E., Petrella, E. C., Cummings, M. D., et al. (2004) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2004.11.009 · Cited by 170 · see citing works
Structure-Based Design of Novel Inhibitors of the MDM2–p53 Interaction
Rew, Y., Sun, D., de Turiso, F. G.-L., Bartberger, M. D., Beck, H. P., Canon, J. R., Chen, A., Chow, D. T., Deignan, J., Fox, B. M., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300354j · Cited by 166 · see citing works
Self-citationThe Structure‐Based Design of Mdm2/Mdmx–p53 Inhibitors Gets Serious
Popowicz, G. M., Dömling, A. S. S., & Holak, T. A. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201003863 · Cited by 166 · see citing works
Novel reactivity of stabilized methylenetributylphosphorane: A new mitsunobu reagent
Tsunoda, T., Ozaki, F., & Itô, S. (1994) · Tetrahedron Letters · doi:10.1016/s0040-4039(00)73326-0 · Cited by 87 · see citing works
Small-Molecule Inhibitors of the p53-MDM2 Interaction
Vu, B. T., & Vassilev, L. T. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_110 · Cited by 78 · see citing works
Parks, D. J., LaFrance, L. V., Calvo, R. R., Milkiewicz, K. L., Marugán, J., Raboisson, P., Schubert, C., Koblish, H. K., Zhao, S., Franks, C. F., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.03.055 · Cited by 76 · see citing works
NMR structure of a complex between MDM2 and a small molecule inhibitor
Fry, D. C., Emerson, S. D., Palme, S., Vu, B. T., Liu, C., & Podlaski, F. (2004) · Journal of Biomolecular NMR · doi:10.1023/b:jnmr.0000048856.84603.9b · Cited by 75 · see citing works
Inhibitors of the p53/hdm2 protein–protein interaction—path to the clinic
Carry, J., & Garcı́a-Echeverrı́a, C. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.03.034 · Cited by 73 · see citing works
Furet, P., Chêne, P., Pover, A. D., Stachyra, T., Lisztwan, J. H., Kallen, J. A., & Masuya, K. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.03.083 · Cited by 73 · see citing works
1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity
Huang, Y., Wolf, S., Biśta, M., Meireles, L., Camacho, C. J., Holak, T. A., & Dömling, A. S. S. (2010) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2010.00989.x · Cited by 65 · see citing works
An Expeditious Synthesis of the MDM2–p53 Inhibitor AM-8553
Lucas, B. S., Fisher, B., McGee, L. R., Olson, S. H., Medina, J. C., & Cheung, E. Y. (2012) · Journal of the American Chemical Society · doi:10.1021/ja305123v · Cited by 45 · see citing works
Self-citationSohmiya, H., Kimura, T., Fujita, M., & Ando, T. (1998) · Tetrahedron · doi:10.1016/s0040-4020(98)00844-8 · Cited by 27 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Genomic classification of cutaneous melanoma
Akbani, R., Akdemir, K. C., Aksoy, B. A., Albert, M., Ally, A., Amin, S. B., Arachchi, H., Arora, A., Auman, J. T., Ayala, B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.05.044 · Cited by 3,151 · see citing works
Molecular Docking and Structure-Based Drug Design Strategies
Ferreira, L. L. G., dos Santos, R. N., Oliva, G., & Andricopulo, A. D. (2015) · Molecules · doi:10.3390/molecules200713384 · Cited by 2,642 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016 · see citing works
Lu, H., Zhou, Q., He, J., Jiang, Z., Peng, C., Tong, R., & Shi, J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00315-3 · Cited by 891 · see citing works
Drugging p53 in cancer: one protein, many targets
Hassin, O., & Oren, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00571-8 · Cited by 736 · see citing works
Understanding the complexity of p53 in a new era of tumor suppression
Liu, Y., Su, Z., Tavana, O., & Gu, W. J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.009 · Cited by 519 · see citing works
Zhao, Y., Aguilar, A., Bernard, D., & Wang, S. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501092z · Cited by 462 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
p53 modifications: exquisite decorations of the powerful guardian
Liu, Y., Tavana, O., & Gu, W. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz060 · Cited by 392 · see citing works
MDM2 inhibition: an important step forward in cancer therapy
Konopleva, M. Y., Martinelli, G., Daver, N. G., Papayannidis, C., Wei, A. H., Higgins, B., Ott, M., Mascarenhas, J. O., & Andreeff, M. (2020) · Leukemia · doi:10.1038/s41375-020-0949-z · Cited by 376 · see citing works
Li, Y., Yang, J., Aguilar, A., McEachern, D., Przybranowski, S., Liu, L., Yang, C.-Y., Wang, M., Han, X., & Wang, S. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00909 · Cited by 312 · see citing works
Targeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges
Wang, S., Zhao, Y., Aguilar, A., Bernard, D., & Yang, C.-Y. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026245 · Cited by 300 · see citing works
The Roles of MDM2 and MDMX in Cancer
Karni-Schmidt, O., Lokshin, M., & Prives, C. L. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040349 · Cited by 294 · see citing works
Tisato, V., Voltan, R., Gonelli, A., Secchiero, P., & Zauli, G. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0500-5 · Cited by 255 · see citing works
Modulation of Protein–Protein Interactions for the Development of Novel Therapeutics
Πέττα, Ι., Lievens, S., Libert, C., Tavernier, J. H., & Bosscher, K. D. (2015) · Molecular Therapy · doi:10.1038/mt.2015.214 · Cited by 240 · see citing works
Drugging Undruggable Molecular Cancer Targets
Lazo, J. S., & Sharlow, E. R. (2015) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103440 · Cited by 225 · see citing works
Zhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., Jiang, Y., Yao, K., & Zhou, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01314-3 · Cited by 223 · see citing works
Aguilar, A., Lu, J., Liu, L., Du, D., Bernard, D., McEachern, D., Przybranowski, S., Li, X., Luo, R., Wen, B., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01665 · Cited by 211 · see citing works
Self-citationTherapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?
Gopalakrishnan, R., Frolov, A. I., Knerr, L., Drury, W. J., & Valeur, E. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00376 · Cited by 169 · see citing works
Therapeutics targeting p53-MDM2 interaction to induce cancer cell death
Koo, N., Sharma, A. K., & Narayan, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095005 · Cited by 153 · see citing works
Canon, J., Osgood, T., Olson, S. H., Saiki, A. Y., Robertson, R., Yu, D., Eksterowicz, J., Ye, Q., Jin, L., Chen, A., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0710 · Cited by 152 · see citing works
Self-citationMDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future
Wang, W., Albadari, N. G., Du, Y., Fowler, J. F., Sang, H. T., Xian, W., McKeon, F., Li, W., Zhou, J., & Zhang, R. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.123.001026 · Cited by 147 · see citing works
Self-citationTP53 in bone and soft tissue sarcomas
Thoenen, E. A., Curl, A., & Iwakuma, T. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.06.010 · Cited by 137 · see citing works
Inhibition of p53 inhibitors: progress, challenges and perspectives
Sanz, G., Singh, M., Peuget, S., & Selivanova, G. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz075 · Cited by 137 · see citing works
Suehara, Y., Alex, D., Bowman, A., Middha, S., Zehir, A., Chakravarty, D., Wang, L., Jour, G., Nafa, K., Hayashi, T., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-4032 · Cited by 135 · see citing works
Liu, Y., Wang, X., Wang, G., Yang, Y., Yuan, Y., & Ouyang, L. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.018 · Cited by 133 · see citing works
Gluck, W. L., Gounder, M. M., Frank, R., Eskens, F., Blay, J. Y., Cassier, P. A., Soria, J.-C., Chawla, S., de Weger, V., Wagner, A. J., et al. (2020) · Investigational New Drugs · doi:10.1007/s10637-019-00840-1 · Cited by 127 · see citing works
Discovery of a Small Molecule MDM2 Inhibitor (AMG 232) for Treating Cancer
Rew, Y., & Sun, D. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500627s · Cited by 125 · see citing works
Self-citationPal, S., Bhattacharjee, A., Ali, A., Mandal, N. C., Mandal, S. C., & Pal, M. (2014) · Journal of Inflammation · doi:10.1186/1476-9255-11-23 · Cited by 117 · see citing works
Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery
Macalino, S. J. Y., Basith, S., Clavio, N. A. B., Chang, H., Kang, S., & Choi, S. (2018) · Molecules · doi:10.3390/molecules23081963 · Cited by 113 · see citing works
The role of TP53 in acute myeloid leukemia: Challenges and opportunities
Barbosa, K., Li, S., Adams, P. D., & Deshpande, A. J. (2019) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22796 · Cited by 115 · see citing works
Kozakov, D., Hall, D. R., Napoleon, R. L., Yueh, C., Whitty, A., & Vajda, S. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00586 · Cited by 111 · see citing works
Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry
Caille, S., Cui, S., Faul, M. M., Mennen, S. M., Tedrow, J. S., & Walker, S. D. (2019) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.9b00735 · Cited by 108 · see citing works
Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives
Fang, Y., Liao, G., & Yu, B. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.003 · Cited by 106 · see citing works
Pearson, C. M., Fyfe, J. W. B., & Snaddon, T. N. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201905426 · Cited by 103 · see citing works
Erba, H. P., Becker, P. S., Shami, P. J., Grunwald, M. R., Flesher, D., Zhu, M., Rasmussen, E., Henary, H. A., Anderson, A., & Wang, E. S. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019030916 · Cited by 103 · see citing works
Small-molecule MDM2 inhibitors in clinical trials for cancer therapy
Wang, S., & Chen, F. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114334 · Cited by 102 · see citing works
Estrada‐Ortiz, N., Neochoritis, C. G., & Dömling, A. S. S. (2015) · ChemMedChem · doi:10.1002/cmdc.201500487 · Cited by 100 · see citing works
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response
Park, D. E., Cheng, J., Berrios, C. J., Montero, J., Cortés-Cros, M., Ferretti, S., Arora, R., Tillgren, M. L., Gokhale, P. C., & DeCaprio, J. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818798116 · Cited by 99 · see citing works
Gupta, A., Bharadwaj, M., Kumar, A., & Mehrotra, R. (2016) · Topics in Current Chemistry · doi:10.1007/s41061-016-0089-0 · Cited by 94 · see citing works
mTOR inhibition and p53 activation, microRNAs: The possible therapy against pandemic COVID-19
Ramaiah, M. J. (2020) · Gene Reports · doi:10.1016/j.genrep.2020.100765 · Cited by 90 · see citing works
Zhang, H., Xu, J., Long, Y., Maimaitijiang, A., Su, Z., Li, W., & Li, J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312928 · Cited by 92 · see citing works
Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction
González, A. Z., Eksterowicz, J. E., Bartberger, M. D., Beck, H. P., Canon, J. R., Chen, A., Chow, D. T., Duquette, J., Fox, B. M., Fu, J., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401767k · Cited by 84 · see citing works
Self-citationMedicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction
Lemos, A., Leão, M., Soares, J., Palmeira, A., Pinto, M. M. M., Saraiva, L., & Sousa, M. E. (2016) · Medicinal Research Reviews · doi:10.1002/med.21393 · Cited by 83 · see citing works
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
LaPlante, G., & Zhang, W. (2021) · Cancers · doi:10.3390/cancers13123079 · Cited by 82 · see citing works
Reviving the guardian of the genome: Small molecule activators of p53
Nguyen, D., Liao, W., Zeng, S. X., & Lu, H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.03.013 · Cited by 80 · see citing works
Development of selective small molecule MDM2 degraders based on nutlin
Wang, B., Wu, S., Liu, J., Yang, K., Xie, H., & Tang, W. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.046 · Cited by 77 · see citing works
Self-citationProlonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells
Skalniak, Ł., Kocik-Krol, J., Polak, J., Skalniak, A., Rak, M., Wolnicka-Głubisz, A., & Holak, T. A. (2018) · Cancers · doi:10.3390/cancers10110396 · Cited by 76 · see citing works
Targeted Degradation of MDM2 as a New Approach to Improve the Efficacy of MDM2-p53 Inhibitors
Wurz, R. P., & Cee, V. J. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01945 · Cited by 75 · see citing works
Current strategies and progress for targeting the “undruggable” transcription factors
Zhuang, J., Liu, Q., Wu, D., & Tie, L. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00852-9 · Cited by 72 · see citing works
Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells
Her, N.-G., Oh, J.-W., Oh, Y. J., Han, S., Cho, H. J., Lee, Y., Ryu, G. H., & Nam, D.-H. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0825-1 · Cited by 68 · see citing works
Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries
Wang, B., Liu, J., Tandon, I., Wu, S., Teng, P., Liao, J., & Tang, W. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113425 · Cited by 67 · see citing works
Self-citationPROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective
Han, X., Wei, W., & Sun, Y. (2022) · Acta Materia Medica · doi:10.15212/amm-2022-0010 · Cited by 67 · see citing works
Hároníková, L., Bonczek, O., Zatloukalová, P., Kokas, F. Z., Kucerikova, M., Coates, P. J., Fåhræus, R., & Vojtěšek, B. (2021) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-021-00293-6 · Cited by 71 · see citing works
AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein–Protein Interaction Interfaces
Rooklin, D. W., Wang, C., Katigbak, J., Arora, P. S., & Zhang, Y. (2015) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5b00103 · Cited by 66 · see citing works
Role of p53 circuitry in tumorigenesis: A brief review
Niazi, S., Purohit, M., & Niazi, J. H. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.08.099 · Cited by 65 · see citing works
Liao, G., Yang, D., Ma, L., Li, W., Hu, L., Zeng, L., Wu, P., Duan, L., & Liu, Z. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.09.044 · Cited by 63 · see citing works
The role of the MDM2/p53 axis in antitumor immune responses
Brummer, T., & Zeiser, R. (2023) · Blood · doi:10.1182/blood.2023020731 · Cited by 63 · see citing works
The p53/MDM2/MDMX-targeted therapies – a clinical synopsis
Jiang, L., & Zawacka-Pankau, J. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-2445-9 · Cited by 62 · see citing works
Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy
Zhang, Z., Ding, Q., Liu, J.-J., Zhang, J., Jiang, N., Chu, X.-J., Bartkovitz, D., Luk, K.-C., Janson, C., Tovar, C., et al. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.05.072 · Cited by 60 · see citing works
Self-citationMDM2: current research status and prospects of tumor treatment
Yao, Y., Zhang, Q., Li, Z., & Zhang, H. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03356-8 · Cited by 66 · see citing works
Self-citationDesign and synthesis of new bioisosteres of spirooxindoles (MI-63/219) as anti-breast cancer agents
Kumar, A., Gupta, G., Bishnoi, A. K., Saxena, R., Saini, K. S., Konwar, R., Kumar, S., & Dwivedi, A. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.12.037 · Cited by 60 · see citing works
Recent Small-Molecule Inhibitors of the p53–MDM2 Protein–Protein Interaction
Beloglazkina, A. A., Zyk, N. V., Majouga, A. G., & Beloglazkina, E. K. (2020) · Molecules · doi:10.3390/molecules25051211 · Cited by 59 · see citing works
Coleman, N., & Rodon, J. A. (2021) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_325885 · Cited by 58 · see citing works
Studying protein–protein interactions: Latest and most popular approaches
Akbarzadeh, S., Coşkun, Ö., & Günçer, B. (2024) · Journal of Structural Biology · doi:10.1016/j.jsb.2024.108118 · Cited by 58 · see citing works
Small-Molecule MDM2-p53 Inhibitors: Recent Advances
Zhang, B., Golding, B. T., & Hardcastle, I. R. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.13 · Cited by 58 · see citing works
When the guardian sleeps: Reactivation of the p53 pathway in cancer
Merkel, O., Taylor, N., Prutsch, N., Staber, P. B., Moriggl, R., Turner, S. D., & Kenner, L. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.02.003 · Cited by 54 · see citing works
González, A. Z., Li, Z., Beck, H. P., Canon, J. R., Chen, A., Chow, D. T., Duquette, J., Eksterowicz, J. E., Fox, B. M., Fu, J., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401911v · Cited by 58 · see citing works
Self-citationChessari, G., Hardcastle, I. R., Ahn, J. S., Anil, B., Anscombe, E., Bawn, R. H., Bevan, L., Blackburn, T. J., Buck, I. M., Cano, C., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02188 · Cited by 58 · see citing works
Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Weisberg, E., Halilovic, E., Cooke, V. G., Nonami, A., Ren, T., Sanda, T., Simkin, I., Yuan, J., Antonakos, B., Barys, L., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0429 · Cited by 56 · see citing works
Qin, J., Wang, W., Voruganti, S., Wang, H., Zhang, W., & Zhang, R. (2014) · Oncotarget · doi:10.18632/oncotarget.3098 · Cited by 56 · see citing works
Saiki, A. Y., Caenepeel, S., Yu, D., Lofgren, J. A., Osgood, T., Robertson, R., Canon, J., Su, C., Jones, A., Zhao, X., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1918 · Cited by 55 · see citing works
Self-citationCierpicki, T., & Grembecka, J. (2015) · Immunological Reviews · doi:10.1111/imr.12244 · Cited by 53 · see citing works
Amino sulfonic acids, peptidosulfonamides and other related compounds
Grygorenko, O. O., Biitseva, A. V., & Zhersh, S. (2018) · Tetrahedron · doi:10.1016/j.tet.2018.01.033 · Cited by 53 · see citing works
An Update on MDMX and Dual MDM2/X Inhibitors
Espadinha, M., Barcherini, V., Lopes, E. A., & Santos, M. M. M. (2018) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026618666180604080119 · Cited by 49 · see citing works
Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Chandramohan, A., Josien, H. B., Yuen, T. Y., Duggal, R., Spiegelberg, D., Yan, L. Y., Juang, Y.-C. A., Ge, L., Aronica, P. G. A., Kaan, H. Y. K., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-43346-4 · Cited by 51 · see citing works
Targeting transcription factors in acute myeloid leukemia
Takei, H., & Kobayashi, S. S. (2018) · International Journal of Hematology · doi:10.1007/s12185-018-2488-1 · Cited by 45 · see citing works
Kocik, J., Machula, M., Wisniewska, A., Surmiak, E., Holak, T. A., & Skalniak, L. (2019) · Cancers · doi:10.3390/cancers11071014 · Cited by 46 · see citing works
Small molecule activators of the p53 response
Ladds, M. J. G. W., & Laı́n, S. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz006 · Cited by 46 · see citing works
Small-molecule inhibition of MDM2-p53 interaction augments radiation response in human tumors
Werner, L. R., Huang, S., Francis, D. M., Armstrong, E. A., Ma, F., Li, C., Iyer, G., Canon, J., & Harari, P. M. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-1056-t · Cited by 45 · see citing works
Self-citationWong, J. H., Alfatah, M., Sin, M. F., Sim, H. M., Verma, C. S., Lane, D. P., & Arumugam, P. (2017) · BMC Biology · doi:10.1186/s12915-017-0446-7 · Cited by 45 · see citing works
Metal-free photosensitized aminosulfonylation of alkenes: a practical approach to β-amido sulfones
Chen, M., Sun, W., Yang, J., Yuan, L., Chen, J., & Wu, J. (2023) · Green Chemistry · doi:10.1039/d3gc01059g · Cited by 45 · see citing works
Potential Therapeutic Targets in Uterine Sarcomas
Cuppens, T., Tuyaerts, S., & Amant, F. C. (2015) · Sarcoma · doi:10.1155/2015/243298 · Cited by 45 · see citing works
Rew, Y., Sun, D., Yan, X., Beck, H. P., Canon, J. R., Chen, A., Duquette, J., Eksterowicz, J. E., Fox, B. M., Fu, J., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501550p · Cited by 45 · see citing works
Self-citationA therapeutic patent overview of MDM2/X-targeted therapies (2014–2018)
Skalniak, Ł., Surmiak, E., & Holak, T. A. (2019) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2019.1582645 · Cited by 45 · see citing works
Small-molecule correctors and stabilizers to target p53
Fallatah, M. M. J., Law, F. V., Chow, W. A., & Kaiser, P. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.02.007 · Cited by 44 · see citing works
Soares, J., Raimundo, L., Pereira, N. A. L., dos Santos, D. J. V. A., Pérez, M., Queiróz, G., Leão, M., Santos, M. M. M., & Saraiva, L. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.03.006 · Cited by 43 · see citing works
Dembla, V., Somaiah, N., Barata, P. C., Hess, K. R., Fu, S., Jankú, F., Karp, D. D., Naing, A., Piha-Paul, S. A., Subbiah, V., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.26075 · Cited by 41 · see citing works
Verstovsek, S., Al-Ali, H. K., Mascarenhas, J., Perkins, A., Vannucchi, A. M., Mohan, S. R., Scott, B. L., Woszczyk, D., Koschmieder, S., García-Delgado, R., et al. (2022) · Future Oncology · doi:10.2217/fon-2022-0901 · Cited by 41 · see citing works
The Role of MDM2 in Promoting Genome Stability versus Instability
Saadatzadeh, M. R., Elmi, A. N., Pandya, P. H., Bijangi‐Vishehsaraei, K., Ding, J., Stamatkin, C. W., Cohen‐Gadol, A., & Pollok, K. E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102216 · Cited by 43 · see citing works
Moreira, J., Almeida, J., Saraiva, L., Cidade, H. M., & Pinto, M. M. M. (2021) · Molecules · doi:10.3390/molecules26123737 · Cited by 41 · see citing works
Identifying the determinants of response to MDM2 inhibition
Saiki, A. Y., Caenepeel, S. R., Cosgrove, E. J., Su, C., Boedigheimer, M. J., & Oliner, J. D. (2015) · Oncotarget · doi:10.18632/oncotarget.3116 · Cited by 39 · see citing works
Self-citationRepurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations
Tang, Y., Song, H., Wang, Z., Xiao, S., Xiang, X., Zhan, H., Wu, L., Wu, J., Xing, Y., Tan, Y., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110622 · Cited by 37 · see citing works
Kang, M. H., Reynolds, C. P., Kolb, E. A., Gorlick, R., Carol, H., Lock, R., Keir, S. T., Maris, J. M., Wu, J., Lyalin, D., et al. (2016) · Pediatric Blood & Cancer · doi:10.1002/pbc.26064 · Cited by 36 · see citing works
An MDM2 degrader for treatment of acute leukemias
Marcellino, B. K., Yang, X., Kanıskan, H. Ü., Brady, C., Chen, H., Chen, K., Qiu, X., Clementelli, C., Herschbein, L., Li, Z., et al. (2022) · Leukemia · doi:10.1038/s41375-022-01735-6 · Cited by 36 · see citing works
Self-citationLi, W., Peng, X., Lang, J., & Xu, C. S. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00631 · Cited by 36 · see citing works
Gicquel, M., Gomez, C., Garcia Alvarez, M. C., Pamlard, O., Guérineau, V., Jacquet, E., Bignon, J., Voituriez, A., & Marinetti, A. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01137 · Cited by 34 · see citing works
Chemical Variations on the p53 Reactivation Theme
Ribeiro, C. J. A., Rodrigues, C. M. P., Moreira, R., & Santos, M. M. M. (2016) · Pharmaceuticals · doi:10.3390/ph9020025 · Cited by 35 · see citing works
Li, R., Zatloukalová, P., Müller, P., Gil-Mir, M., Kote, S., Wilkinson, S., Kemp, A. J., Hernychová, L., Wang, Y., Ball, K. L., et al. (2020) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-020-00233-w · Cited by 34 · see citing works
Self-citation
- Authors
- Sun, D., Li, Z., Rew, Y., Gribble, M., Bartberger, M. D., Beck, H. P., Canon, J., Chen, A., Chen, X., Chow, D., Deignan, J., Duquette, J., Eksterowicz, J., Fisher, B., Fox, B. M., Fu, J., Gonzalez, A. Z., Gonzalez-Lopez De Turiso, F., Houze, J. B., Huang, X., Jiang, M., Jin, L., Kayser, F., Liu, J. (., Lo, M.-C., Long, A. M., Lucas, B., McGee, L. R., McIntosh, J., Mihalic, J., Oliner, J. D., Osgood, T., Peterson, M. L., Roveto, P., Saiki, A. Y., Shaffer, P., Toteva, M., Wang, Y., Wang, Y. C., Wortman, S., Yakowec, P., Yan, X., Ye, Q., Yu, D., Yu, M., Zhao, X., Zhou, J., Zhu, J., Olson, S. H., & Medina, J. C.
- Affiliations
- Amgen (United States) (US)
- Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California, 94080, United States
- Corresponding author
- Sun, Daqing
- ORCID
- Sun, Daqing
- Li, Zhihong
- Rew, Yosup
- Gribble, Michael
- Bartberger, Michael D.
- Beck, Hilary P.
- Canon, Jude
- Chen, Ada
- Chow, David
- Huang, Xin
- Jiang, Min
- Jin, Lixia
- Liu, Jiwen (Jim)
- Lo, Mei-Chu
- Lucas, Brian
- McIntosh, Joel
- Oliner, Jonathan D.
- Osgood, Tao
- Roveto, Philip
- Saiki, Anne Y.
- Shaffer, Paul
- Wang, Yingcai
- Yan, Xuelei
- Ye, Qiuping
- Yu, Dongyin
- Zhao, Xiaoning
- Zhou, Jing
- Olson, Steven H.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-02-05
- Volume
- 57
- Issue
- 4
- Pages
- 1454-1472
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2090240238
- Cited by
- 290
- References
- 26
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 16 · 2023: 31 · 2022: 30 · 2021: 34 · 2020: 20 · 2019: 30 · 2018: 23 · 2017: 14 · 2016: 12 · 2015: 25 · 2014: 15
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p53-MDM2 interaction, MDM2 inhibitors, piperidinone, sulfones, N-alkyl substituents, oral bioavailability, pharmacokinetics, anticancer activity, osteosarcoma, anticancer drug discovery
- MeSH terms
- Acetates, Administration, Oral, Antineoplastic Agents, Biological Availability, Humans, Piperidones, Protein Conformation, Tumor Suppressor Protein p53, Crystallography, X-Ray, Proto-Oncogene Proteins c-mdm2, Drug Discovery
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
