Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020)

References

• Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–349.
   PubMed Web of Science ®Google Scholar
• Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–837.
   PubMed Web of Science ®Google Scholar
• Laugesen A, Hojfeldt JW, Helin K. Role of the polycomb repressive complex 2 (PRC2) in transcriptional regulation and cancer. Cold Spring Harb Perspect Med. 2016;6:9.
   Web of Science ®Google Scholar
• Margueron R, Li G, Sarma K, et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell. 2008;32(4):503–518.
   PubMed Web of Science ®Google Scholar
• Qi W, Zhao K, Gu J, et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol. 2017;13(4):381–388.
   PubMed Web of Science ®Google Scholar
• Huang Y, Zhang J, Yu Z, et al. Discovery of first-in-class, potent, and orally bioavailable embryonic ectoderm development (EED) inhibitor with robust anticancer efficacy. J Med Chem. 2017;60(6):2215–2226.
   PubMed Web of Science ®Google Scholar
• Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004;15(1):57–67.
   PubMed Web of Science ®Google Scholar
• Nekrasov M, Wild B, Müller J. Nucleosome binding and histone methyltransferase activity of Drosophila PRC2. EMBO Rep. 2005;6(4):348–353.
   PubMed Web of Science ®Google Scholar
• Poepsel S, Kasinath V, Nogales E. Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes. Nat Struct Mol Biol. 2018;25(2):154–162.
   PubMed Web of Science ®Google Scholar
• Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–185.
   PubMed Web of Science ®Google Scholar
• Li B, Chng W-J. EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications. J Hematol Oncol. 2019;12(1):118.
   PubMed Web of Science ®Google Scholar
• Kim KH, Kim W, Howard TP, et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med. 2015;21(12):1491–1496.
   PubMed Web of Science ®Google Scholar
• Italiano A. Targeting epigenetics in sarcomas through EZH2 inhibition. J Hematol Oncol. 2020;13(1):33.
   PubMed Web of Science ®Google Scholar
• Wang X, Brea LT, Yu J. Immune modulatory functions of EZH2 in the tumor microenvironment: implications in cancer immunotherapy. Am J Clin Exp Urol. 2019;7(2):85–91.
   PubMed Web of Science ®Google Scholar
• Ueda T, Sanada M, Matsui H, et al. EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms. Leukemia. 2012;26(12):2557–2560.
   PubMed Web of Science ®Google Scholar
• Stazi G, Zwergel C, Mai A, et al. EZH2 inhibitors: a patent review (2014-2016). Expert Opin Ther Pat. 2017;27(7):797–813.
   PubMed Web of Science ®Google Scholar
• Arsenijevic Y, Mbefo KM Inhibition of PRC2 subunits to treat eye disorders. WO2020011607A1, 2020.
   Google Scholar
• Zhou J, Huang S, Wang Z, et al. Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation. Nat Commun. 2019;10(1):1–11.
   PubMed Web of Science ®Google Scholar
• Rohraff DM, He Y, Farkash EA, et al. Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice. Arthritis Rheumatol. 2019;71(10):1681–1690.
   PubMed Web of Science ®Google Scholar
• Li J, Hart RP, Mallimo EM, et al. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat Neurosci. 2013;16(12):1745–1753.
   PubMed Web of Science ®Google Scholar
• Turner AM, Dronamraju R, Potjewyd FM, et al. Evaluation of EED inhibitors as a class of PRC2-targeted small molecules for HIV latency reversal. ACS Infect Dis. 2020.
   PubMed Web of Science ®Google Scholar
• Cacace A, Thompson LA III, Lin L, et al. Compositions and methods for increasing gene FMR1 expression. WO2018170290A1, 2018.
   Google Scholar
• Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013;110(19):7922–7927.
   PubMed Web of Science ®Google Scholar
• FDA approves first treatment option specifically for patients with epithelioid sarcoma, a rare soft tissue cancer [News release]. [cited 24 Mar]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-option-specifically-patients-epithelioid-sarcoma-rare-soft-tissue
   Google Scholar
• A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adult subjects with ini1-negative tumors or relapsed/refractory synovial sarcoma. Available from: https://ClinicalTrials.gov/show/NCT02601950.
   Google Scholar
• Constellation pharmaceuticals presentation highlights enhanced EZH2 target engagement, leading to second-generation EZH2 inhibitor CPI-0209 [News Release]. [cited 16 Jun]. Available from: http://ir.constellationpharma.com/news-releases/news-release-details/constellation-pharmaceuticals-presentation-highlights-enhanced.
   Google Scholar
• Open-label, multicenter, phase 1/2 study of tazemetostat (EZH2 histone methyl transferase HMT inhibitor) as a single agent in subjects With Adv. Solid tumors or with B-cell lymphomas and tazemetostat in combination with prednisolone in subjects with DLBCL. Available from: https://ClinicalTrials.gov/show/NCT01897571.
   Google Scholar
• Epizyme announces the U.S. food and drug administration lifts partial clinical hold on tazemetostat clinical program [press release]. [cited 27 Mar.]. Available from: https://epizyme.gcs-web.com/news-releases/news-release-details/epizyme-announces-us-food-and-drug-administration-lifts-partial
   Google Scholar
• A phase 1b/2 open-label study in chemotherapy naive subjects with metastatic castration-resistant prostate cancer. Available from: https://ClinicalTrials.gov/show/NCT04179864.
   Google Scholar
• Tazemetostat an pembrolizumab in treating patients with locally advanced or metastatic urothelial carcinoma. Available from: https://ClinicalTrials.gov/show/NCT03854474.
   Google Scholar
• A study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2816126 in Subjects with relapsed/refractory diffuse large B cell lymphoma, transformed follicular lymphoma, other non-hodgkin’s lymphomas, solid tumors and multiple myeloma. Available from: https://ClinicalTrials.gov/show/NCT02082977.
   Google Scholar
• Huang S, Wang Z, Zhou J, et al. EZH2 inhibitor GSK126 suppresses antitumor immunity by driving production of myeloid-derived suppressor cells. Cancer Res. 2019;79(8):2009–2020.
   PubMed Web of Science ®Google Scholar
• Albrecht BK, Audia JE, Cook AS, et al. Preparation of heteroaryl amides as modulators of methyl modifying enzymes. WO2013120104A2, 2013.
   Google Scholar
• A study evaluating CPI-1205 in patients with B-cell lymphomas. Available from: https://ClinicalTrials.gov/show/NCT02395601.
   Google Scholar
• Harb W, Abramson J, Lunning M, et al. 42OA phase 1 study of CPI-1205, a small molecule inhibitor of EZH2, preliminary safety in patients with B-cell lymphomas. Ann Oncol. 2018;29(suppl_3).
   Google Scholar
• Taplin M-E, Hussain A, Shah S, et al. Abstract CT094: phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC). 2019;79(13 Supplement):CT094–CT094.
   Google Scholar
• ProSTAR: a study evaluating CPI-1205 in patients with metastatic castration resistant prostate cancer. Available from: https://ClinicalTrials.gov/show/NCT03480646.
   Google Scholar
• Goswami S, Apostolou I, Zhang J, et al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest. 2018;128(9):3813–3818.
   PubMed Web of Science ®Google Scholar
• ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer. https://ClinicalTrials.gov/show/NCT03480646.
   Google Scholar
• ORIOn-E: A Study Evaluating CPI-1205 in Patients With Advanced Solid Tumors. https://ClinicalTrials.gov/show/NCT03525795.
   Google Scholar
• A Study of CPI-0209 in Patients With Advanced Solid Tumors. https://ClinicalTrials.gov/show/NCT04104776.
   Google Scholar
• DS-3201b for Acute Myelogenous Leukemia (AML) or Acute Lymphocytic Leukemia (ALL). https://ClinicalTrials.gov/show/NCT03110354.
   Google Scholar
• DS-3201b and Irinotecan for Patients With Recurrent Small Cell Lung Cancer. https://ClinicalTrials.gov/show/NCT03879798.
   Google Scholar
• DS-3201b in Participants With Lymphomas. https://ClinicalTrials.gov/show/NCT02732275.
   Google Scholar
• Valemetostat Tosylate (DS-3201b) Phase 2 Study in Relapsed or Refractory Adult T-cell Leukemia/Lymphoma. https://ClinicalTrials.gov/show/NCT04102150.
   Google Scholar
• Study of Single-dose DS-3201b in Participants With Hepatic Impairment. https://ClinicalTrials.gov/show/NCT04276662.
   Google Scholar
• A Phase 1 Study of SHR2554 in Subjects With Relapsed or Refractory Mature Lymphoid Neoplasms. https://ClinicalTrials.gov/show/NCT03603951.
   Google Scholar
• A Study of SHR2554 Alone or in Combination With SHR3680 in the Treatment of mCRPC. https://ClinicalTrials.gov/show/NCT03741712.
   Google Scholar
• PF-06821497 Treatment Of Relapsed/Refractory SCLC, Castration Resistant Prostate Cancer, and Follicular Lymphoma. https://ClinicalTrials.gov/show/NCT03460977.
   Google Scholar
• Khanna A, Côté A, Arora S, et al. Pharmacological evaluation of second generation EZH2 inhibitors with long residence time. ACS Med Chem Lett. 2020;11(6):1205–1212.
   PubMed Web of Science ®Google Scholar
• Brenneman JB, Cote A, Gehling VS, et al. Modulators of methyl modifying enzymes, compositions and uses thereof. WO2019094552A1, 2019.
   Google Scholar
• Cote A, Khanna A, Moine L Preparation of substituted dioxoloisoquinolinones as modulators of methyl modifying enzymes. WO2019226491A1, 2019.
   Google Scholar
• A study of CPI-0209 in patients with advanced solid tumors. Available from: https://ClinicalTrials.gov/show/NCT04104776.
   Google Scholar
• Relations CPI, Constellation pharmaceuticals presentation highlights enhanced EZH2 target engagement, leading to second-generation EZH2 inhibitor CPI-0209. 2019.
   Google Scholar
• Keller PJ, Feng Zhao RM, Linlin M, et al., Targeting epigenetic dysregulation in bladder cancer through inhibition of EZH2. In American Association for Cancer Research Bladder Cancer, Denver, Colorado; 2019.
   Google Scholar
• Constellation pharmaceuticals provides updates of MANIFEST study for CPI-0610 and EZH2 Franchise [News Release]. [cited 17 Jul]. Available from: ir.constellationpharma.com/news-releases/news-release-details/constellation-pharmaceuticals-provides-updates-manifest-study.
   Google Scholar
• Kanno O, Watanabe J, Horiuchi T, et al. Preparation of 1,3-benzodioxole derivatives, EZH1 and/or EZH2 inhibitors, and pharmaceuticals containing them for treatment of cancer. WO2015141616A1, 2015.
   Google Scholar
• Honma D, Kanno O, Watanabe J, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017;108(10):2069–2078.
   PubMed Web of Science ®Google Scholar
• Daiichi Sankyo’s EZH1/2 dual inhibitor valemetostat (DS-3201) receives SAKIGAKE designation for treatment of patients with relapsed/refractory peripheral T-cell lymphoma from Japan MHLW. [cited 24 Nov]. Available from: https://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006996.html.
   Google Scholar
• Lu B, Shen X, He M, et al. Preparation of benzofuran derivative as EZH2 inhibitor for treating cancer. WO2017084494A1, 2017.
   Google Scholar
• Kung -P-P, Rui E, Bergqvist S, et al. Design and synthesis of pyridone-containing 3,4-Dihydroisoquinoline-1(2H)-ones as a novel class of enhancer of zeste homolog 2 (EZH2) inhibitors. J Med Chem. 2016;59(18):8306–8325.
   PubMed Web of Science ®Google Scholar
• Kung -P-P, Bingham P, Brooun A, et al. Optimization of orally bioavailable enhancer of Zeste Homolog 2 (EZH2) inhibitors using ligand and property-based design strategies: identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497). J Med Chem. 2018;61(3):650–665.
   PubMed Web of Science ®Google Scholar
• Knight SD, Newlander KA, Tian X Preparation of N-oxopyridinylmethyl thiophenecarboxamides as enhancer of zeste homolog 2 inhibitors. WO2016066697A1; 2016.
   Google Scholar
• Knight SD, Lafrance LV III, Tian X Preparation of dihydropiperidinyl tetrahydrothienoazepinones as enhancer of zeste homolog 2 inhibitors for the treatment of cancer. WO2017191545A1; 2017.
   Google Scholar
• Brackley JA III, Graves AP III, Knight SD, et al. Preparation of oxopyridinylmethyl thienopyridinones and thienoazepinones as enhancer of zeste homolog 2 inhibitors. WO2017002064A1; 2017.
   Google Scholar
• Guo D, Yu K-L Preparation of N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl]-4-methylthiophene-3-carboxamide and its isomer as inhibitors of EXH2. WO2016089804A1; 2016.
   Google Scholar
• Dominguez E, Guo D, Mader MM, et al. Preparation of 1,2-dihydropyridinylmethyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one compounds as EZH2 inhibitors for treatment of cancer. WO2017035060A1; 2017.
   Google Scholar
• Marx MA, Lee MR, Galemmo RA; N-Heterobicyclylmethyl-3,4-dihydroisoquinolin-1(2H)-ones as EZH2 inhibitors and their preparation. US20180265517A1; 2018.
   Google Scholar
• Bradner JE, Paulk J, Qi J. Preparation of histone methyltransferase EZH2 inhibitors useful for treatment of cancer, inflammation, and other diseases. WO2017184999A1; 2017.
   Google Scholar
• Brooun A, Gajiwala KS, Deng YL, et al. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat Commun. 2016;7:11384.
   PubMed Web of Science ®Google Scholar
• Si J, Wang G, Jiang M, et al. Preparation of pyridine derivatives as histone methyltransferase EZH2 inhibitors. WO2018137639A1; 2018.
   Google Scholar
• Liu QS, Liu J, Lv F, et al. EZH2 inhibitor and use thereof. WO2018133795A1; 2018.
   Google Scholar
• Peng W, Xian J, Hu Y, et al. Polysubstituted benzene compound and preparation method and use thereof. WO2020020374A1; 2020.
   Google Scholar
• Chen X, Chen Y, Huang Y, et al. Preparation of indolizine compounds for treatment of cancer and autoimmune diseases. WO2019170063A1; 2019.
   Google Scholar
• Chen X, Geng M, Jiang L, et al. Pyrido five-element aromatic ring compound, preparation method therefor and use thereof. WO2018045971A1; 2018.
   Google Scholar
• Konze KD, Ma A, Li F, et al. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324–1334.
   PubMed Web of Science ®Google Scholar
• Fernandez-Montalvan AE, Stresemann C, Christ C, et al. Preparation of quinoline derivatives as EZH2 inhibitors. WO2017025493A1, 2017.
   Google Scholar
• Zhou F, Shi X, Wang L, et al. Process for preparation of 1,5,7-tri-substituted isoquinoline derivatives and use in medicines. WO2018086589A1, 2018.
   Google Scholar
• Jin Y, Chen X, Cheng P, et al. Sulfonyl-substituted benzoheterocyclic derivative as EZH2 inhibitor and its preparation. WO2018086590A1, 2018.
   Google Scholar
• Peng J, Liu Y, Wang L, et al. 4,5,6-Tri-substituted indazoles derivatives, preparation method and medical application. WO2018086592A1, 2018.
   Google Scholar
• Jiang T, Zhao S, Li J, et al. Ezh2 inhibitor and pharmaceutically acceptable salts, polymorphic crystal, and application. WO2019206155A1, 2019.
   Google Scholar
• Bisserier M, Wajapeyee N. Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas. Blood. 2018;131(19):2125–2137.
   PubMed Web of Science ®Google Scholar
• Safety and efficacy of MAK683 in adult patients with advanced malignancies. Available from: https://ClinicalTrials.gov/show/NCT02900651.
   Google Scholar
• Chan HM, Gu X-J-J, Huang Y, et al. Preparation of triazolopyrimidine compounds useful in the treatment of diseases or disorders mediated by EED and/or PRC2. WO2016103155A1, 2016.
   Google Scholar
• Liu B, Huang Y, Mao L, et al. Preparation of crystalline forms of N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]-8-(2-methylpyridin-3-yl)-1,2,4-triazolo[4,3-c]pyrimidin-5-amine hydrochloride useful in the treatment of diseases or disorders mediated by EED and/or PRC2. WO2017219948A1, 2017.
   Google Scholar
• Li L, Zhang H, Zhang M, et al. Discovery and molecular basis of a diverse set of polycomb repressive complex 2 inhibitors recognition by EED. PLoS One. 2017;12(1):e0169855.
   PubMed Web of Science ®Google Scholar
• Lingel A, Sendzik M, Huang Y, et al. Structure-guided design of EED binders allosterically inhibiting the epigenetic polycomb repressive complex 2 (PRC2) methyltransferase. J Med Chem. 2017;60(1):415–427.
   PubMed Web of Science ®Google Scholar
• Chan HM, Fu X, Gu X-J-J, et al. Preparation of triazolopyridine compounds useful in the treatment of diseases or disorders mediated by EED and/or PRC2. WO2017221092A1, 2017.
   Google Scholar
• Chan HM, Fu X, Gu X-J-J, et al. Imidazopyrimidine compounds useful for the treatment of cancer and their preparation. WO2017221100A1, 2017.
   Google Scholar
• He Y, Selvaraju S, Curtin ML, et al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 2017;13(4):389–395.
   PubMed Web of Science ®Google Scholar
• Michaelides MR, Curtin ML, Li H-Q, et al. Preparation of indane inhibitors of EED. US20170320880A1, 2017.
   Google Scholar
• Curtin ML, Pliushchev MA, Li HQ, et al. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. Bioorg Med Chem Lett. 2017;27(7):1576–1583.
   PubMed Web of Science ®Google Scholar
• Wang Y, Edalji RP, Panchal SC, et al. Are we there yet? Applying thermodynamic and kinetic profiling on embryonic ectoderm development (EED) hit-to-lead program. J Med Chem. 2017;60(20):8321–8335.
   PubMed Web of Science ®Google Scholar
• Huang D, Tian S, Qi Y, et al. Binding modes of small-molecule inhibitors to the EED pocket of PRC2. Chemphyschem. 2020;21(3):263–271.
   PubMed Web of Science ®Google Scholar
• Zhou B, Luo C, Yang Y, et al. Use of triazolopyrimidine, triazolopyridine compounds and composition thereof for treating PRC2-mediated diseases. WO2019062435A1, 2019.
   Google Scholar
• Zhou B, Luo C, Yang Y, et al. Triazolopyrimidine derivative compound, pharmaceutical composition comprising same and use thereof. WO2019158025A1, 2019.
   Google Scholar
• Marx MA, Lee MR, Bobinski TP, et al. Preparation of dihydrobenzofuranylmethylaminoimidazopyrimidine derivatives for use as PRC2 inhibitors. WO2019152419A1, 2019.
   Google Scholar
• Zou B, Ma S, Fu X, et al. Preparation of the pyrimidone compound and their application as the anticancer agents. WO2019120276A1, 2019.
   Google Scholar
• Dong H, Liu S, Zhang X, et al. An allosteric PRC2 inhibitor targeting EED suppresses tumor progression by modulating the immune response. Cancer Res. 2019;79(21):5587–5596.
   PubMed Web of Science ®Google Scholar
• Zou B, Ma S, Wang X, et al. Pyridine or pyridazine cyclic compound and application thereof in preparing drugs for treating cancer diseases or disorders. CN110563722A, 2019.
   Google Scholar
• Zou B, Ma S, Wang X, et al. Pyrimidine- or pyrazine-based compound and application thereof. CN110734436A; 2020.
   Google Scholar
• Zhang H, Liu K, Yan X, et al. Determination and evaluation of novel small molecule inhibitor for EED-EZH2 interaction. CN110950834A; 2020.
   Google Scholar
• Zhang H, Liu K, Yan X, et al. Small molecule inhibitor of EED-EZH2 interaction and its application in the treatment of malignant lymphoma. CN110960525A, 2020.
   Google Scholar
• Zhu K, Yang R, Tao H, et al. Identification and assessments of novel and potent small-molecule inhibitors of EED-EZH2 interaction of polycomb repressive complex 2 by computational methods and biological evaluations. Chem Pharm Bull (Tokyo). 2020;68(1):58–63.
   PubMed Web of Science ®Google Scholar
• Barnash KD, The J, Norris-Drouin JL, et al. Discovery of peptidomimetic ligands of EED as allosteric inhibitors of PRC2. ACS Comb Sci. 2017;19(3):161–172.
   PubMed Web of Science ®Google Scholar
• Read JA, Rawlins PB, Tart J, et al. Rapid identification of novel allosteric PRC2 inhibitors. ACS Chem Biol. 2019;14(10):2134–2140.
   PubMed Web of Science ®Google Scholar
• Rej RK, Wang C, Lu J, et al. Structure-based discovery of a highly potent and orally active small-molecule inhibitor of embryonic ectoderm development (EED) capable of achieving complete tumor regression. 2020. American Chemical Society. pp MEDI-0180.
   Google Scholar
• Morressier Structure-based discovery of a highly potent and orally active small-molecule inhibitor of embryonic ectoderm development (EED) capable of achieving complete tumor regression. [cited 2020 Jun 16]. Available from: https://www.morressier.com/article/structurebased-discovery-highly-potent-orally-active-smallmolecule-inhibitor-embryonic-ectoderm-development-eed-capable-achieving-complete-tumor-regression/5e736c72cde2b641284ac06a.
   Google Scholar
• Catalano R, Costa G, Maruca A, et al. A drug repurposing screening reveals a novel epigenetic activity of hydroxychloroquine. Eur J Med Chem. 2019;183:111715.
   PubMed Web of Science ®Google Scholar
• Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16(2):101–114.
   PubMed Web of Science ®Google Scholar
• Neklesa TK, Crews CM. Chemical biology: greasy tags for protein removal. Nature. 2012;487(7407):308–309.
   PubMed Web of Science ®Google Scholar
• Yang X, Li F, Konze KD, et al. Structure–activity relationship studies for enhancer of zeste homologue 2 (EZH2) and enhancer of zeste homologue 1 (EZH1) inhibitors. J Med Chem. 2016;59(16):7617–7633.
   PubMed Web of Science ®Google Scholar
• Jian Jin RP, Stratikopoulos I, Yang X Compositions and methods for treating ezh2-mediated cancer. 2017.
   Google Scholar
• Lu J, Qian Y, Altieri M, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol. 2015;22(6):755–763.
   PubMedGoogle Scholar
• Ma A, Stratikopoulos E, Park KS, et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020;16(2):214–222.
   PubMed Web of Science ®Google Scholar
• Crew AP, Jing Wang LBS, Dong H, et al. Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide. June 28 2018.
   Google Scholar
• Buckley DL, Van Molle I, Gareiss PC, et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction. J Am Chem Soc. 2012;134(10):4465–4468.
   PubMed Web of Science ®Google Scholar
• Wang X, Cao W, Zhang J, et al. A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination. Embo J. 2017;36(9):1243–1260.
   PubMed Web of Science ®Google Scholar
• Schapira M, Calabrese MF, Bullock AN, et al. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov. 2019;18(12):949–963.
   PubMed Web of Science ®Google Scholar
• Potjewyd F, Turner AW, Beri J, et al. Degradation of polycomb repressive complex 2 with an EED-targeted bivalent chemical degrader. Cell Chem Biol. 2020;27(1):47–56.e15.
   PubMed Web of Science ®Google Scholar
• Hsu JH, Rasmusson T, Robinson J, et al. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex. Cell Chem Biol. 2020;27(1):41–46.e17.
   PubMed Web of Science ®Google Scholar
• An S, Fu L. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine. 2018;36:553–562.
   PubMed Web of Science ®Google Scholar