Dual-target EZH2 Inhibitor: Latest Advances in Medicinal Chemistry

Overview

Journal Future Med Chem

Specialties Chemistry
Pharmacy

Date 2024 Jul 31

PMID 39082677

Authors

Lai Wei

Dan Mei

Sijia Hu

Shufang Du

Affiliations

Soon will be listed here.

Abstract

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, plays a crucial role in tumor progression by regulating gene expression. EZH2 inhibitors have emerged as promising anti-tumor agents due to their potential in cancer treatment strategies. However, single-target inhibitors often face limitations such as drug resistance and side effects. Dual-target inhibitors, exemplified by EZH1/2 inhibitor HH-2853(), offer enhanced efficacy and reduced adverse effects. This review highlights recent advancements in dual inhibitors targeting EZH2 and other proteins like BRD4, PARP1, and EHMT2, emphasizing rational design, structure-activity relationships, and safety profiles, suggesting their potential in clinical applications.

References

Dawicki-McKenna J, Langelier M, DeNizio J, Riccio A, Cao C, Karch K . PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain. Mol Cell. 2015; 60(5):755-768. PMC: 4712911. DOI: 10.1016/j.molcel.2015.10.013. View

Krifa M, Leloup L, Ghedira K, Mousli M, Chekir-Ghedira L . Luteolin induces apoptosis in BE colorectal cancer cells by downregulating calpain, UHRF1, and DNMT1 expressions. Nutr Cancer. 2014; 66(7):1220-7. DOI: 10.1080/01635581.2014.951729. View

Zheng X, Li W, Yi J, Liu J, Ren L, Zhu X . EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers. Acta Pharmacol Sin. 2020; 42(7):1171-1179. PMC: 8209002. DOI: 10.1038/s41401-020-00543-x. View

Beguelin W, Popovic R, Teater M, Jiang Y, Bunting K, Rosen M . EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5):677-92. PMC: 3681809. DOI: 10.1016/j.ccr.2013.04.011. View

Shankar E, Franco D, Iqbal O, Moreton S, Kanwal R, Gupta S . Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer. Toxicol Appl Pharmacol. 2020; 404:115200. DOI: 10.1016/j.taap.2020.115200. View

An R, Li Y, Lin Y, Xu F, Li M, Liu Z . EZH1/2 as targets for cancer therapy. Cancer Gene Ther. 2022; 30(2):221-235. DOI: 10.1038/s41417-022-00555-1. View

Yang D, Liu H, Yang Z, Fan D, Tang Q . BMI1 in the heart: Novel functions beyond tumorigenesis. EBioMedicine. 2021; 63:103193. PMC: 7804972. DOI: 10.1016/j.ebiom.2020.103193. View

Aoyama K, Oshima M, Koide S, Suzuki E, Mochizuki-Kashio M, Kato Y . Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome. iScience. 2018; 9:161-174. PMC: 6223231. DOI: 10.1016/j.isci.2018.10.008. View

Cho H, Kelly J, Hayami S, Toyokawa G, Takawa M, Yoshimatsu M . Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia. 2011; 13(8):676-84. PMC: 3156658. DOI: 10.1593/neo.11512. View

10.

Gibaja V, Shen F, Harari J, Korn J, Ruddy D, Saenz-Vash V . Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene. 2015; 35(5):558-66. PMC: 4744243. DOI: 10.1038/onc.2015.114. View

11.

Jin X, Kim L, Wu Q, Wallace L, Prager B, Sanvoranart T . Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. Nat Med. 2017; 23(11):1352-1361. PMC: 5679732. DOI: 10.1038/nm.4415. View

12.

Yuan Z, Chen W, You B, Liu Y, Yang S, Li J . Multifunctional nanoparticles co-delivering EZH2 siRNA and etoposide for synergistic therapy of orthotopic non-small-cell lung tumor. J Control Release. 2017; 268:198-211. DOI: 10.1016/j.jconrel.2017.10.025. View

13.

Fioravanti R, Stazi G, Zwergel C, Valente S, Mai A . Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds. Chem Rec. 2018; 18(12):1818-1832. PMC: 7410397. DOI: 10.1002/tcr.201800091. View

14.

Gao B, Liu X, Li Z, Zhao L, Pan Y . Overexpression of EZH2/NSD2 Histone Methyltransferase Axis Predicts Poor Prognosis and Accelerates Tumor Progression in Triple-Negative Breast Cancer. Front Oncol. 2021; 10:600514. PMC: 7921704. DOI: 10.3389/fonc.2020.600514. View

15.

Wu L, Gong Y, Yan T, Zhang H . LINP1 promotes the progression of cervical cancer by scaffolding EZH2, LSD1, and DNMT1 to inhibit the expression of KLF2 and PRSS8. Biochem Cell Biol. 2020; 98(5):591-599. DOI: 10.1139/bcb-2019-0446. View

16.

Deng K, Zou Y, Zou C, Wang H, Xiang Y, Yang X . Study on pharmacokinetic interactions between SHR2554 and itraconazole in healthy subjects: A single-center, open-label phase I trial. Cancer Med. 2022; 12(2):1431-1440. PMC: 9883540. DOI: 10.1002/cam4.5028. View

17.

Guo Z, Sun Y, Liang L, Lu W, Luo B, Wu Z . Design and Synthesis of Dual EZH2/BRD4 Inhibitors to Target Solid Tumors. J Med Chem. 2022; 65(9):6573-6592. DOI: 10.1021/acs.jmedchem.1c01876. View

18.

Yuan W, Wu T, Fu H, Dai C, Wu H, Liu N . Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation. Science. 2012; 337(6097):971-5. DOI: 10.1126/science.1225237. View

19.

Zhang S, Liao W, Wu Q, Huang X, Pan Z, Chen W . LINC00152 upregulates ZEB1 expression and enhances epithelial-mesenchymal transition and oxaliplatin resistance in esophageal cancer by interacting with EZH2. Cancer Cell Int. 2020; 20(1):569. PMC: 7690072. DOI: 10.1186/s12935-020-01620-1. View

20.

Guryanova O, Wu Q, Cheng L, Lathia J, Huang Z, Yang J . Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell. 2011; 19(4):498-511. PMC: 3076106. DOI: 10.1016/j.ccr.2011.03.004. View