Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

In the paper

“SYVN1 is lowly expressed in proliferating B cells and moderately expressed in some differentiated B cells, i.e., centrocytes, but highly expressed in plasmocytes (Fig. 3), suggesting that its expression is upregulated during B cell differentiation.”

In the paper

“Besides the E3 ligases discussed above, there are many other cell type-specific E3 ligases identified at the single-cell level (Fig. 3), such as KCTD12 in blood dendritic cells, and TRIM22 in blood plasmacytoid dendritic cells.”

In the paper

“KRT8 is highly expressed in cells in gastrointestinal tract, prostate, and pancreas, but lowly expressed in cells of brain and hematopoietic system (Additional file 1).”

In the paper

“BCR-ABL is an oncogenic fusion protein implicated in the development of chronic myelogenous leukemia (CML) [74].”

What the sources say

• Not checked yetcites [74] Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33–44. source

In the paper

“DT2216, a representative PROTAC that hijacks the VHL E3 ligase to achieve tissue/cell-selective degradation of Bcl-xL, was found to be more potent against Bcl-xL-dependent tumor cells and less toxic against platelets in comparison to conventional Bcl-xL inhibitors.”

What the sources say

• Not checked yetcites [4] Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. source

In the paper

“Mcl-1 is upregulated in various hematologic malignancies (e.g., multiple myeloma (MM) and AML) and some solid tumors (e.g., hepatocellular carcinoma and NSCLC) [64].”

What the sources say

• Not checked yetcites [64] Fletcher S. MCL-1 inhibitors - where are we now (2019)? Expert Opin Ther Pat. 2019;29:909–19. source

In the paper

“Although the PROTAC molecules could degrade Bcl-6 in a number of cells, they did not improve antiproliferative activity over Bcl-6 inhibitors in DLBCL cells.”

What the sources say

• Not checked yetcites [42] McCoull W, Cheung T, Anderson E, Barton P, Burgess J, Byth K, et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC to provide insight into small molecule targeting of BCL6. ACS Chem Biol. 2018;13:3131–41. source

In the paper

“Third, PROTACs can be used to overcome drug resistance resulting from mutations of a POI or compensatory increase in POI induced by SMIs [3].”

What the sources say

• Not checked yetcites [3] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17. source

In the paper

“Because of this unique mechanism of action (MOA), PROTACs produce longer and stronger biological effects than SMIs on a target”

In the paper

“However, due to the challenge of disrupting PPI, these Bcl-6 inhibitors have suffered from low potency [72] and thus have limited clinical application.”

What the sources say

• Not checked yetcites [72] Sameshima T, Yamamoto T, Sano O, Sogabe S, Igaki S, Sakamoto K, et al. Discovery of an irreversible and cell-active BCL6 inhibitor selectively targeting Cys53 located at the protein-protein interaction interface. Biochemistry. 2018;57:1369–79. source

In the paper

“Considering these limitations of using monoclonal antibodies and TNAs, PROTACs have a better chance for faster clinical development against a broader range of targets in multiple tumor types.”

In the paper

“Moreover, DT2216 potently degraded Bcl-xL protein and inhibited MOLT-4 T-ALL in vitro and in vivo.”

What the sources say

• Not checked yetcites [4] Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. source

In the paper

“By degrading Bcl-6 via the UPS, BI-3802 displayed stronger de-repression of target genes than Bcl-6 inhibitors and demonstrated antiproliferative effects in several DLBCL cell lines [73].”

What the sources say

• Not checked yetcites [73] Kerres N, Steurer S, Schlager S, Bader G, Berger H, Caligiuri M, et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep. 2017;20:2860–75. source

In the paper

“SIAIS178 potently degraded BCR-ABL protein (DC50 = 8.5 nM) and inhibited the proliferation of K562 cells (EC50 = 24 nM), and further efficiently inhibited tumor growth and induced BCR-ABL degradation in K562 xenografts.”

What the sources say

• Not checked yetcites [6] Zhao Q, Ren C, Liu L, Chen J, Shao Y, Sun N, et al. Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. J Med Chem. 2019;62:9281–98. source

In the paper

“It is broadly expressed in many lymphomas and plays a significant role in lymphomagenesis by being involved in the formation of germinal centers (GCs) during the humoral immune response [66–69].”

What the sources say

• Not checked yetcites [66] Cardenas MG, Oswald E, Yu W, Xue F, MacKerell AD, Melnick AM. The expanding role of the BCL6 oncoprotein as a cancer therapeutic target. Clin Cancer Res. 2017;23:885–93. source
• Not checked yetcites [67] Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997;276:589–92. source
• Not checked yetcites [68] Fukuda T, Yoshida T, Okada S, Hatano M, Miki T, Ishibashi K, et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med. 1997;186:439–48. source
• Not checked yetcites [69] Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-Centre formation and Th2-type inflammation. Nat Genet. 1997;16:161–70. source

In the paper

“These Bcl-xL degraders showed significantly reduced cytotoxicity against platelets but improved killing of various tumor cells and senescent cells due to differential expression of these E3 ligases”

What the sources say

• Not checked yetcites [60] He Y, Zhang X, Chang J, Kim H-N, Zhang P, Wang Y, et al. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat Commun. 2020;11:1996. source
• Not checked yetcites [61] Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur J Med Chem. 2020;199:112397. source
• Not checked yetcites [62] Zhang X, Thummuri D, Liu X, Hu W, Zhang P, Khan S, et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur J Med Chem. 2020;192:112186. source
• Not checked yetcites [63] Zhang X, Thummuri D, He Y, Liu X, Zhang P, Zhou D, et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL, 55. Chem Commun (Camb). 2019:14765–8. source

In the paper

“However, TKIs need to be administered continuously for life to treat CML patients likely due to the scaffolding functions of BCR-ABL that activate compensatory signaling pathways to promote the survival of leukemic stem cells (LSCs) [76, 77].”

What the sources say

• Not checked yetcites [76] Ichim CV. Kinase-independent mechanisms of resistance of leukemia stem cells to tyrosine kinase inhibitors. Stem Cells Transl Med. 2014;3:405–15. source
• Not checked yetcites [77] Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119:1501–10. source

In the paper

“Mutations in the FLT-3 gene have been found in patients with ALL (1–3%), myelodysplasia (5–10%), and AML (15–35%), making it one of the most frequently mutated genes in hematologic malignancies [128].”

What the sources say

• Not checked yetcites [128] Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–65. source

In the paper

“YX-2-107, a CRBN-recruiting PROTAC, degraded CDK6 selectively in Ph-like and MLL-rearranged cell lines, and inhibited their proliferation.”

In the paper

“Rao’s group reported a BTK degrader, named P13I, which efficiently degraded both wild-type and C418S BTK with DC50 values of 10 nM and 28 nM, respectively.”

What the sources say

• Not checked yetcites [117] Sun Y, Zhao X, Ding N, Gao H, Wu Y, Yang Y, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018;28:779–81. source

In the paper

“TD-428 possesses two unique properties: high specificity and lacking the Hook effect.”

What the sources say

• Not checked yetcites [110] Kim SA, Go A, Jo S-H, Park SJ, Jeon YU, Kim JE, et al. A novel cereblon modulator for targeted protein degradation. Eur J Med Chem. 2019;166:65–74. source

In the paper

“MT-802, but not ibrutinib, was found to reduce activated-BTK levels in patient-derived CLL cells harboring the C481S mutation [116].”

What the sources say

• Not checked yetcites [116] Buhimschi AD, Armstrong HA, Toure M, Jaime-Figueroa S, Chen TL, Lehman AM, et al. Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57:3564–75. source

In the paper

“QCA570 is the most potent BET PROTAC that displays picomolar potency against human acute leukemia cell lines in vitro and in vivo [93].”

What the sources say

• Not checked yetcites [93] Qin C, Hu Y, Zhou B, Fernandez-Salas E, Yang C-Y, Liu L, et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J Med Chem. 2018;61:6685–704. source

In the paper

“only selectively induce BRD3/4 degradation without any effect on BRD2, but still possess the anti-proliferation effect against AML cells [89].”

What the sources say

• Not checked yetcites [89] Chan K-H, Zengerle M, Testa A, Ciulli A. Impact of target warhead and linkage vector on inducing protein degradation: comparison of bromodomain and extra-terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds. J Med Chem. 2018;61:504–13. source

In the paper

“These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.”

In the paper

“BSJ-03-123, a CRBN-based CDK6 degrader, was reported to selectively degrade CDK6 but not CDK4 in AML cell lines because it can form a ternary complex with CDK6 and CRBN but not with CDK4 and CRBN [121].”

What the sources say

• Not checked yetcites [121] Brand M, Jiang B, Bauer S, Donovan KA, Liang Y, Wang ES, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem Biol. 2019;26:300–306.e9. source

In the paper

“Later, ARV-825 and ARV-771 were tested widely and displayed potent in vitro and in vivo efficacies against AML [104, 105], post-myeloproliferative neoplasm secondary AML [106, 107], MM [108], mantle cell lymphoma (MCL) [8], and DLBCL [109].”

What the sources say

• Not checked yetcites [104] Mill CP, Fiskus W, DiNardo CD, Qian Y, Raina K, Rajapakshe K, et al. RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1. Blood. 2019;134:59–73. source
• Not checked yetcites [105] Piya S, Mu H, Bhattacharya S, Lorenzi PL, Davis RE, McQueen T, et al. BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment. J Clin Invest. 2019;129:1878–94. source
• Not checked yetcites [106] Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31:1951–61. source
• Not checked yetcites [107] Saenz DT, Fiskus W, Mill CP, Perera D, Manshouri T, Lara BH, et al. Mechanistic basis and efficacy of targeting the β-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors. Blood. 2020;135:1255–69. source
• Not checked yetcites [108] Zhang X, Lee HC, Shirazi F, Baladandayuthapani V, Lin H, Kuiatse I, et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia. 2018;32:2224–39. source

In the paper

“Bruton’s tyrosine kinase (BTK) is involved in constitutively active B cell receptor (BCR) signaling in various B cell malignancies CLL, DLBCL, and MCL, and thus, is an important therapeutic target in these malignancies [112].”

What the sources say

• Not checked yetcites [112] Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123:1207–13. source

In the paper

“BETd-260 exerted high potency to rapidly degrade BRD2/3/4 and inhibit the growth of RS4-11 B cell acute lymphoblastic leukemia (B-ALL) cells in vitro and in a mouse xenograft model [92].”

What the sources say

• Not checked yetcites [92] Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, et al. Discovery of a small-molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J Med Chem. 2018;61:462–81. source

In the paper

“The RN486-based degrader, named DD-04-015, efficiently and selectively degraded BTK and produced a similar antiproliferative activity as RN486 in BTK-dependent TMD8 DLBCL cells.”

What the sources say

• Not checked yetcites [115] Huang H-T, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25:88–99.e6. source

In the paper

“A1874), which not only degrades BRD4, but also stabilizes p53, and exhibited high anti-proliferative effect in several tumor cell lines including BL and myeloid leukemia [95].”

What the sources say

• Not checked yetcites [95] Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 2019;79:251–62. source

In the paper

“In addition, long-term dosing or high concentrations associated with BETi treatment also leads to obvious BRD4 protein accumulation and inefficient c-MYC suppression [85].”

What the sources say

• Not checked yetcites [85] Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol. 2015;22:755–63. source

In the paper

“Wu et al. proposed that HDAC6-IKZFs dual degraders would achieve an enhanced anti-myeloma activity based on the synergistic effect of HDAC6 inhibitors and immunomodulatory imide drugs (IMiDs) [11].”

What the sources say

• Not checked yetcites [11] Wu H, Yang K, Zhang Z, Leisten ED, Li Z, Xie H, et al. Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity. J Med Chem. 2019;62:7042–57. source

In the paper

“In an early study, using a CRBN-recruiting PROTAC based on a promiscuous kinase inhibitor to target multiple kinases failed to significantly degrade FLT-3, likely due to its poor cell permeability [115].”

What the sources say

• Not checked yetcites [115] Huang H-T, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25:88–99.e6. source

In the paper

“In addition, both the FLT-3 PROTAC and inhibitor were ineffective against other types of hematologic malignancies, such as K562 CML cells, suggesting that the antitumor effect of the FLT-3 PROTAC on different FLT-3 ITD mutated cells is cell-dependent.”

What the sources say

• Not checked yetcites [10] Burslem GM, Song J, Chen X, Hines J, Crews CM. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion. J Am Chem Soc. 2018;140:16428–32. source

In the paper

“As expected, MD-224 can only inhibit the growth of leukemia cells carrying the wild-type P53 but not those with P53 mutants [46].”

What the sources say

• Not checked yetcites [46] Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem. 2019;62:448–66. source

In the paper

“Several MDM2 SMIs including nutlins (nutlin 1, nutlin 2, nutlin 3) and their derivatives have been developed and exhibit good activities against various solid and hematologic malignancies, but can also cause hematopoietic suppression and gastrointestinal toxicity [144].”

What the sources say

• Not checked yetcites [144] Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017;10:133. source

In the paper

“EZH2 acts as the core catalytic subunit of PRC2, and EED and SUZ12 subunits are indispensable for EZH2 catalytic activity [151].”

What the sources say

• Not checked yetcites [151] Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43. source

In the paper

“Overexpression of MDM2 has been often observed in various human cancers and can contribute to tumorigenesis [142, 143].”

What the sources say

• Not checked yetcites [142] Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A. 1998;95:15608–12. source
• Not checked yetcites [143] Teoh G, Urashima M, Ogata A, Chauhan D, DeCaprio JA, Treon SP, et al. MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells. Blood. 1997;90:1982–92. source

In the paper

“The degradation effect of this PROTAC was more significant on HDAC1-2 in comparison to HDAC3, which can probably be attributed to the HDAC binding preference of the warhead.”

What the sources say

• Not checked yetcites [140] Smalley JP, Adams GE, Millard CJ, Song Y, Norris JKS, Schwabe JWR, et al. PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes, Chem Commun (Camb). 2020;56:4476–9. source

In the paper

“HDAC6 seems to be very sensitive to PROTAC-mediated degradation, probably because of its dominant cytoplasmic localization, whereas most other isoforms are localized in the nucleus [139].”

What the sources say

• Not checked yetcites [139] Boyault C, Sadoul K, Pabion M, Khochbin S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene. 2007;26:5468–76. source

In the paper

“Most of the approved drugs have limited isoform selectivity and none of the drug candidates have achieved clinical success for treating solid tumors as a single agent, which is probably due to their inability to achieve high concentrations in solid tumor tissues.”

What the sources say

• Not checked yetcites [133] Guha M. HDAC inhibitors still need a home run, despite recent approval. Nat Rev Drug Discov. 2015;14:225–6. source
• Not checked yetcites [134] Gryder BE, Sodji QH, Oyelere AK. Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Med Chem. 2012;4:505–24. source

In the paper

“MDM2 is a known E3 ubiquitin ligase that acts as a powerful inhibitor of the tumor suppressor P53 [141].”

What the sources say

• Not checked yetcites [141] Kruse J-P, Gu W. Modes of p53 regulation. Cell. 2009;137:609–22. source

In the paper

“However, the in vitro anti-proliferative activity of the FLT-3 PROTAC varies among AML cells compared to the FLT-3 inhibitor that was used to develop the PROTAC. For example, the PROTAC exerted a significantly better activity against MV4-11 and wild-type MOLM-14 AML cells, but was less potent in OCI-AML3 cells, than the FLT-3 inhibitor, which is likely attributed to the extent of kinase engagement”

What the sources say

• Not checked yetcites [10] Burslem GM, Song J, Chen X, Hines J, Crews CM. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion. J Am Chem Soc. 2018;140:16428–32. source

In the paper

“Mu et al. reported a CRBN-based BRD4/PLK1 dual degrader, HBL-4, which is more potent than its parental inhibitor BI2536 [145].”

What the sources say

• Not checked yetcites [145] Mu X, Bai L, Xu Y, Wang J, Lu H. Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells. Biochem Biophys Res Commun. 2020;521:833–9. source

In the paper

“Achieving a complete and sustained inhibition of FLT-3 ITD signaling to maintain effective clinical response requires a high dose of inhibitors, which leads to off-target toxicities [131].”

What the sources say

• Not checked yetcites [131] Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance. Int J Hematol. 2013;97:683–94. source

In the paper

“In addition, MDM2 inhibitor can lead to a significant compensatory increase in MDM2 expression, which can lead rapid degradation of p53 upon clearance of the MDM2 [46].”

What the sources say

• Not checked yetcites [46] Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem. 2019;62:448–66. source

In the paper

“By converting an HDACi into an isoform-selective HDAC PROTAC, it is possible to achieve improved potency and reduced off-target toxicity as reported recently [11, 135–138].”

What the sources say

• Not checked yetcites [11] Wu H, Yang K, Zhang Z, Leisten ED, Li Z, Xie H, et al. Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity. J Med Chem. 2019;62:7042–57. source
• Not checked yetcites [135] Yang K, Wu H, Zhang Z, Leisten ED, Nie X, Liu B, et al. Development of selective histone deacetylase 6 (HDAC6) degraders recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. ACS Med Chem Lett. 2020;11:575–81. source
• Not checked yetcites [136] Yang K, Song Y, Xie H, Wu H, Wu Y-T, Leisten ED, et al. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg Med Chem Lett. 2018;28:2493–7. source
• Not checked yetcites [137] Yang H, Lv W, He M, Deng H, Li H, Wu W, et al. Plasticity in designing PROTACs for selective and potent degradation of HDAC6. Chem Commun (Camb). 2019;55:14848–51. source
• Not checked yetcites [138] An Z, Lv W, Su S, Wu W, Rao Y. Developing potent PROTACs tools for selective degradation of HDAC6 protein. Protein Cell. 2019;10:606–9. source

In the paper

“The oncogenic CALR mutant protein could be an excellent PROTAC target to treat MPN patients with CALR mutations.”

In the paper

“However, such inhibitors have failed to inhibit tumor cell growth [48] because the ATPase domain but not the bromodomain is essential for tumor cell growth [169].”

What the sources say

• Not checked yetcites [48] Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019;15:672–80. source
• Not checked yetcites [169] Vangamudi B, Paul TA, Shah PK, Kost-Alimova M, Nottebaum L, Shi X, et al. The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF-mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res. 2015;75:3865–78. source

In the paper

“Several SMIs that block the dimerization of STAT3 have reached the clinical development stage, but only exhibited very limited clinical activity [173].”

What the sources say

• Not checked yetcites [173] Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48. source

In the paper

“CALR mutations are mutually exclusive with JAK2 or MPL mutations in MPNs, suggesting common oncogenic pathways.”

What the sources say

• Not checked yetcites [188] Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405. source
• Not checked yetcites [189] Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90. source
• Not checked yetcites [190] Broséus J, Park J-H, Carillo S, Hermouet S, Girodon F. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood. 2014;124:3964–6. source

In the paper

“NPM1c+ acts as a dominant negative mutant for NPM1 function and has a gain-of-function role in pathogenesis of the AML phenotype [196, 197].”

What the sources say

• Not checked yetcites [196] Bolli N, Nicoletti I, De Marco MF, Bigerna B, Pucciarini A, Mannucci R, et al. Born to be exported: COOH-terminal nuclear export signals of different strength ensure cytoplasmic accumulation of nucleophosmin leukemic mutants. Cancer Res. 2007;67:6230–7. source
• Not checked yetcites [197] Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP, et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood. 2005;106:899–902. source

In the paper

“Brander’s group reported a selective degrader of BRD9, named dBRD9, which efficiently degraded BRD9 and exerted a 10–100-fold increase in antiproliferative activity than the corresponding inhibitor against MOLM-13 and other AML cell lines [180].”

What the sources say

• Not checked yetcites [180] Remillard D, Buckley DL, Paulk J, Brien GL, Sonnett M, Seo H-S, et al. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands. Angew Chem Int Ed Engl. 2017;56:5738–43. source

In the paper

“Meanwhile, SMIs that target the allosteric binding site of the SMARCA2/4 ATPase domain and are orally bioavailable with in vivo antitumor activity have been reported [170].”

What the sources say

• Not checked yetcites [170] Papillon JPN, Nakajima K, Adair CD, Hempel J, Jouk AO, Karki RG, et al. Discovery of orally active inhibitors of brahma homolog (BRM)/SMARCA2 ATPase activity for the treatment of brahma related gene 1 (BRG1)/SMARCA4-mutant cancers. J Med Chem. 2018;61:10155–72. source

In the paper

“Further, SD-36 had desirable PK/pharmacodynamic (PD) properties, was well tolerated and achieved complete and long-lasting tumor regression in mice xenografted with AML and ALCL cell lines.”

What the sources say

• Not checked yetcites [3] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17. source

In the paper

“The most potent compound named PROTAC2 developed by Bloecher’s group selectively degraded EED, EZH2, and SUZ12, and reduced the proliferation of EZH-dependent tumor cells Karpas422 [161].”

What the sources say

• Not checked yetcites [161] Hsu JH-R, Rasmusson T, Robinson J, Pachl F, Read J, Kawatkar S, et al. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex. Cell Chem Biol. 2020;27:41–46.e17. source

In the paper

“The most potent compounds named UNC6852 developed by James’ group also selectively degraded EED, EZH2, and SUZ12, and potently inhibited the proliferation of DLBCL cell lines with a wild-type and Y641N mutant EZH2 [47].”

What the sources say

• Not checked yetcites [47] Potjewyd F, Turner A-MW, Beri J, Rectenwald JM, Norris-Drouin JL, Cholensky SH, et al. Degradation of polycomb repressive complex 2 with an EED-targeted bivalent chemical degrader. Cell Chem Biol. 2020;27:47–56.e15. source

In the paper

“Among the four distinct families of CRCs (SWI/SNF, ISWI, CHD, INO80), SWI/SNF complexes are the most implicated in diseases with more than 20% of human cancers bearing mutations in the genes encoding mammalian SWI/SNF (mSWI/SNF) subunits [163].”

What the sources say

• Not checked yetcites [163] St Pierre R, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev. 2017;42:56–67. source

In the paper

“The development of a PROTAC specifically targeting NPM1c+ could be a superb strategy.”

In the paper

“Aberrant activation of STAT3 is associated with many human malignancies [172–174], because STAT3 regulates numerous genes involved in tumorigenesis, progression, and drug resistance, and thus it has become an attractive cancer target [172].”

What the sources say

• Not checked yetcites [172] Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105. source
• Not checked yetcites [173] Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48. source
• Not checked yetcites [174] Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303. source

In the paper

“Schiedel et al. reported a PROTAC against sirtuin 2 (SIRT2). This PROTAC selectively induced SIRT2 degradation in HeLa cells and led to more pronounced acetylation of the microtubule network than the corresponding inhibitor [177].”

What the sources say

• Not checked yetcites [177] Schiedel M, Herp D, Hammelmann S, Swyter S, Lehotzky A, Robaa D, et al. Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals). J Med Chem. 2018;61:482–91. source

In the paper

“ACBI1 potently induced SMARCA2/4 and PBRM1 degradation in the AML cell line, and inhibited cell growth in multiple cancer cell lines [48].”

What the sources say

• Not checked yetcites [48] Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019;15:672–80. source

In the paper

“Interestingly, although SD-36 also binds to other STAT proteins, such as STAT1 and STAT4, it only degrades STAT3.”

What the sources say

• Not checked yetcites [3] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17. source

In the paper

“CALR mutations has been shown to be pathogenic and serve as a disease-initiating event to favor the expansion of the megakaryocytic lineage by specific activation of the thrombopoietin receptor and uncontrolled activation of the JAK2/STAT pathway [191, 192].”

What the sources say

• Not checked yetcites [191] Marty C, Pecquet C, Nivarthi H, El-Khoury M, Chachoua I, Tulliez M, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016;127:1317–24. source
• Not checked yetcites [192] Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu R-I, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127:1325–35. source

In the paper

“MS1943 could effectively degrade EZH2 and selectively kill EZH2-dependent TNBC cells, whereas EZH2 inhibitors are ineffective in blocking the proliferation of TNBC cells.”

What the sources say

• Not checked yetcites [162] Ma A, Stratikopoulos E, Park K-S, Wei J, Martin TC, Yang X, et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020;16:214–22. source

In the paper

“In addition, PROTACs targeting tripartite motif-containing protein 24 (TRIM24), receptor-interacting protein kinase 2 (RIPK2), and the Janus kinase family enzymes for degradation may also have the potential to be used to treat certain types of hematologic malignancies but require further studies [185–187].”

What the sources say

• Not checked yetcites [185] Gechijian LN, Buckley DL, Lawlor MA, Reyes JM, Paulk J, Ott CJ, et al. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat Chem Biol. 2018;14:405–12. source
• Not checked yetcites [186] Mares A, Miah AH, Smith IED, Rackham M, Thawani AR, Cryan J, et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun Biol. 2020;3:140. source
• Not checked yetcites [187] Shah RR, Redmond JM, Mihut A, Menon M, Evans JP, Murphy JA, et al. Hi-JAK-ing the ubiquitin system: the design and physicochemical optimisation of JAK PROTACs. Bioorg Med Chem. 2020;28:115326. source

In the paper

“Degradation of SMARCA2/4 and PBRM1 subunits may disrupt the integrity of the BAF and PBAF complexes, resulting in the dissociation of other subunits.”

In the paper

“Theoretically, these oncofusion proteins could be ideal PROTAC targets, since they are “alien” to human cells and the side effects would be easier to manage.”

In the paper

“It is encouraging that the PROTACs targeting AR and ER have advanced to the clinic and the preliminary results from these clinical studies reveal that the AR PROTAC ARV-110 appears clinically effective in a patient with metastatic castration-resistant prostate cancer (https://ir.arvinas.com/node/7666/pdf).”

What the sources say

• Not checked yetcites https://ir.arvinas.com/node/7666/pdf

In the paper

“It is well established that chromosomal translocations promote the development of hematologic malignancies either through the formation of oncogenic fusion protein or through oncogene activation by a stronger promoter or enhancer [200, 201].”

What the sources say

• Not checked yetcites [200] Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:233–45. source
• Not checked yetcites [201] Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008;359:722–34. source

In the paper

“Although PROTACs can be more potent than SMIs against a POI, they might produce greater on-target toxicities than SMIs for several reasons. First, SMIs rarely inhibit the functions of their targets completely, while PROTACs can almost entirely deplete their targets.”

In the paper

“These binary complexes can potentially recruit off-targets and lead to their degradation and off-target toxicities.”

In the paper

“Although numerous PROTACs have been generated in the past few years, only a few of them are tumor-selective to avoid normal tissue toxicity, including platelet sparing Bcl-xL PROTACs reported by us recently by taking advantage of the E3 ligases that are barely expressed in platelets [4, 60–63].”

What the sources say

• Not checked yetcites [4] Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. source
• Not checked yetcites [60] He Y, Zhang X, Chang J, Kim H-N, Zhang P, Wang Y, et al. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat Commun. 2020;11:1996. source
• Not checked yetcites [61] Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur J Med Chem. 2020;199:112397. source
• Not checked yetcites [62] Zhang X, Thummuri D, Liu X, Hu W, Zhang P, Khan S, et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur J Med Chem. 2020;192:112186. source
• Not checked yetcites [63] Zhang X, Thummuri D, He Y, Liu X, Zhang P, Zhou D, et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL, 55. Chem Commun (Camb). 2019:14765–8. source

In the paper

“However, high concentrations of PROTACs produce the “Hook effect,” which may lead to the formation of binary complexes of PROTACs and E3 ligases [28].”

What the sources say

• Not checked yetcites [28] Pettersson M, Crews CM. PROteolysis targeting chimeras (PROTACs)—past, present and future. Drug Discov Today Technol. 2019;31:15–27. source

In the paper

“A well-characterized example of off-target activities of PROTACs are CRBN-based PROTACs because CRBN ligands, including thalidomide, pomalidomide, and lenalidomide, used for the CRBN-targeted PROTACs can recruit several neo-substrates such as SALL4, IKZF1, and IKZF3 to CRBN to induce their degradation [207, 208]. This can lead to some adverse effects including teratogenic effect and cardiovascular”

What the sources say

• Not checked yetcites [207] Donovan KA, An J, Nowak RP, Yuan JC, Fink EC, Berry BC, et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane radial ray syndrome. Elife. 2018;7. source
• Not checked yetcites [208] Sievers QL, Petzold G, Bunker RD, Renneville A, Słabicki M, Liddicoat BJ, et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science. 2018;362. source

In the paper

“The oncofusion proteins are often specific for subtype of hematologic malignancies, which also have potential value for PROTAC development in terms of E3 ligase selections, e.g., there are four most prevalent oncofusion proteins in AML: PML-RARα, AML1-ETO, CBFβ-MYH11, and MLL-fusions, while ETV6-RUNX1 and TCF3-PBX1 fusions are common in B-cell ALL [202].”

What the sources say

• Not checked yetcites [202] Rowley JD. Chromosomal translocations: revisited yet again. Blood. 2008;112:2183–9. source

In the paper

“Third, SMIs may cause a transient inhibition of a protein function while PROTACs induce prolonged depletion of the target protein due to their unique MOA.”

In the paper

“These findings are in agreement with Crews’ recent suggestion that developing tumor-specific/selective PROTACs has the potential to reduce the on-target toxicities of PROTACs [2].”

What the sources say

• Not checked yetcites [2] Schapira M, Calabrese MF, Bullock AN, Crews CM. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov. 2019;18:949–63. source

In the paper

“Similarly, the VHL E3 ligase is essential for the ubiquitination and degradation of hypoxia-inducible factor-1 alpha (HIF1a) [209], a TF that regulates many genes necessary for tumor growth. If VHL is overly engaged by a PROTAC, it can potentially inhibit the degradation of HIF1a to promote tumorigenesis.”

What the sources say

• Not checked yetcites [209] Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5. source

In the paper

“An example is BTK, that is important for B cell development and can promote the development of B cell lymphoma [118].”

What the sources say

• Not checked yetcites [118] Sun Y, Ding N, Song Y, Yang Z, Liu W, Zhu J, et al. Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas. Leukemia. 2019;33:2105–10. source

In the paper

“The most challenging step for such PROTAC development will be the screening for relative specific ligands for such oncofusion proteins.”

In the paper

“Second, some POIs have both enzymatic and scaffold functions. The latter may be important for normal cell functions. In this case, in contrast to SMIs which only inhibit enzymatic function, PROTACs can completely deplete the protein, resulting in the loss of both enzymatic activity and scaffolding function, which can potentially cause some undesirable consequences.”

In the paper

“The available crystal structures for some of these oncofusion proteins will aid this endeavor.”

In the paper

“The incomplete inhibition of a POI with SMIs may be tolerable [203], while their complete depletion with a PROTAC might be detrimental if the POI is essential for normal cell function.”

What the sources say

• Not checked yetcites [203] Strelow JM. A perspective on the kinetics of covalent and irreversible inhibition. SLAS Discov. 2017;22:3–20. source

In the paper

“To date, two PROTACs have entered into clinical trials for the treatment of prostate and breast cancers.”

In the paper

“the high molecular weight and complex structure of PROTACs makes some of the PROTACs have low in vivo efficacy.”

In the paper

“Breakthroughs in scRNA-seq have greatly enhanced our ability to determine cell-type specific transcriptomes [12], and enable us to understand the profile of oncogenic targets and E3 ligases at the single-cell level.”

What the sources say

• Not checked yetcites [12] Han X, Zhou Z, Fei L, Sun H, Wang R, Chen Y, et al. Construction of a human cell landscape at single-cell level. Nature. 2020;581:303–9. source

In the paper

“The development of tumor-specific/selective PROTACs based on cell-type and tumor-specific/selective E3 ligases may revolutionize the field of PROTACs as antitumor therapeutics.”

In the paper

“ARV-471 is currently in a phase I clinical trial (NCT04072952).”

In the paper

“ARV-471 is a PROTAC designed to specifically target ER.”

In the paper

“This can be accomplished by profiling E3 ligase expression at a cellular level as discussed below.”

In the paper

“Targeted protein degradation using PROTACs has emerged as a novel therapeutic modality in drug discovery.”

In the paper

“ARV-110 is an orally bioavailable AR PROTAC that entered into a clinical trial to treat patients with metastatic castrate-resistant prostate cancer (NCT03888612) in 2019.”

In the paper

“Based on this, we can choose more specific E3 ligases to target POIs to improve the efficiency of PROTACs and maximally reduce the toxicities to normal cells, which may be particularly applicable for hematologic malignancies.”