Inhibitors of Protein Methyltransferases and Demethylases

Overview

Journal Chem Rev

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Mar 25

PMID 28338320

Citations 126

Authors

H Umit Kaniskan

Michael L Martini

Jian Jin

Affiliations

Soon will be listed here.

Abstract

Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

Citing Articles

The Olive Oil Phenolic -(-)-Oleocanthal Suppresses Colorectal Cancer Progression and Recurrence by Modulating SMYD2-EZH2 and c-MET Activation.

Tarun M, Elsayed H, Ebrahim H, El Sayed K Nutrients. 2025; 17(3).

PMID: 39940255 PMC: 11821053. DOI: 10.3390/nu17030397.

Biomedical effects of protein arginine methyltransferase inhibitors.

Cao M, Nguyen T, Song J, Zheng Y J Biol Chem. 2025; 301(3):108201.

PMID: 39826691 PMC: 11871472. DOI: 10.1016/j.jbc.2025.108201.

Integrating epigenetic modification and stem cell therapy strategies: A novel approach for advancing Alzheimer's disease treatment - A literature review.

Widaja E, Pawitan J Narra J. 2025; 4(3):e935.

PMID: 39816083 PMC: 11731673. DOI: 10.52225/narra.v4i3.202.

Therapeutic targeting potential of the protein lysine and arginine methyltransferases to reverse cancer chemoresistance.

Micallef I, Fenech K, Baron B Front Mol Biosci. 2024; 11:1455415.

PMID: 39703687 PMC: 11656028. DOI: 10.3389/fmolb.2024.1455415.

KDM4A promotes malignant progression of breast cancer by down-regulating BMP9 inducing consequent enhancement of glutamine metabolism.

Chen Y, Yang S, Yu T, Zeng T, Wei L, You Y Cancer Cell Int. 2024; 24(1):322.

PMID: 39300582 PMC: 11414211. DOI: 10.1186/s12935-024-03504-0.

References

Souroullas G, Jeck W, Parker J, Simon J, Liu J, Paulk J . An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016; 22(6):632-40. PMC: 4899144. DOI: 10.1038/nm.4092. View

Mannironi C, Proietto M, Bufalieri F, Cundari E, Alagia A, Danovska S . An high-throughput in vivo screening system to select H3K4-specific histone demethylase inhibitors. PLoS One. 2014; 9(1):e86002. PMC: 3906020. DOI: 10.1371/journal.pone.0086002. View

Southall S, Wong P, Odho Z, Roe S, Wilson J . Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. Mol Cell. 2009; 33(2):181-91. DOI: 10.1016/j.molcel.2008.12.029. View

Cheng D, Valente S, Castellano S, Sbardella G, Di Santo R, Costi R . Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity. J Med Chem. 2011; 54(13):4928-32. PMC: 3487391. DOI: 10.1021/jm200453n. View

Arrowsmith C, Bountra C, Fish P, Lee K, Schapira M . Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov. 2012; 11(5):384-400. DOI: 10.1038/nrd3674. View

Ruger N, Roatsch M, Emmrich T, Franz H, Schule R, Jung M . Tetrazolylhydrazides as Selective Fragment-Like Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A. ChemMedChem. 2015; 10(11):1875-83. DOI: 10.1002/cmdc.201500335. View

Allali-Hassani A, Wasney G, Siarheyeva A, Hajian T, Arrowsmith C, Vedadi M . Fluorescence-based methods for screening writers and readers of histone methyl marks. J Biomol Screen. 2011; 17(1):71-84. DOI: 10.1177/1087057111422256. View

Ferguson A, Larsen N, Howard T, Pollard H, Green I, Grande C . Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011; 19(9):1262-73. DOI: 10.1016/j.str.2011.06.011. View

Ibanez G, McBean J, Astudillo Y, Luo M . An enzyme-coupled ultrasensitive luminescence assay for protein methyltransferases. Anal Biochem. 2010; 401(2):203-10. DOI: 10.1016/j.ab.2010.03.010. View

10.

Swiercz R, Cheng D, Kim D, Bedford M . Ribosomal protein rpS2 is hypomethylated in PRMT3-deficient mice. J Biol Chem. 2007; 282(23):16917-23. DOI: 10.1074/jbc.M609778200. View

11.

Kumarasinghe I, Woster P . Synthesis and evaluation of novel cyclic Peptide inhibitors of lysine-specific demethylase 1. ACS Med Chem Lett. 2014; 5(1):29-33. PMC: 4027766. DOI: 10.1021/ml4002997. View

12.

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

13.

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

14.

Benelkebir H, Hodgkinson C, Duriez P, Hayden A, Bulleid R, Crabb S . Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors. Bioorg Med Chem. 2011; 19(12):3709-16. DOI: 10.1016/j.bmc.2011.02.017. View

15.

Hong H, Kao C, Jeng M, Eble J, Koch M, Gardner T . Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer. 2004; 101(1):83-9. DOI: 10.1002/cncr.20327. View

16.

Cao J, Liu Z, Cheung W, Zhao M, Chen S, Chan S . Histone demethylase RBP2 is critical for breast cancer progression and metastasis. Cell Rep. 2014; 6(5):868-77. PMC: 4014129. DOI: 10.1016/j.celrep.2014.02.004. View

17.

Tzatsos A, Pfau R, Kampranis S, Tsichlis P . Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci U S A. 2009; 106(8):2641-6. PMC: 2650317. DOI: 10.1073/pnas.0813139106. View

18.

Baker T, Nerle S, Pritchard J, Zhao B, Rivera V, Garner A . Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors. Oncotarget. 2015; 6(32):32646-55. PMC: 4741719. DOI: 10.18632/oncotarget.5066. View

19.

Black J, Manning A, Van Rechem C, Kim J, Ladd B, Cho J . KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell. 2013; 154(3):541-55. PMC: 3832053. DOI: 10.1016/j.cell.2013.06.051. View

20.

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View