Chemical biology and pharmacology of histone lysine methylation inhibitors

Samir H Barghout; Raquel Arminda Carvalho Machado; Dalia Barsyte-Lovejoy

doi:10.1016/j.bbagrm.2022.194840

Chemical biology and pharmacology of histone lysine methylation inhibitors

Biochim Biophys Acta Gene Regul Mech. 2022 Aug;1865(6):194840. doi: 10.1016/j.bbagrm.2022.194840. Epub 2022 Jun 24.

Authors

Samir H Barghout¹, Raquel Arminda Carvalho Machado², Dalia Barsyte-Lovejoy³

Affiliations

¹ Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
² Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: d.barsyte@utoronto.ca.

PMID: 35753676
DOI: 10.1016/j.bbagrm.2022.194840

Abstract

Histone lysine methylation is a post-translational modification that plays a key role in the epigenetic regulation of a broad spectrum of biological processes. Moreover, the dysregulation of histone lysine methyltransferases (KMTs) has been implicated in the pathogenesis of several diseases particularly cancer. Due to their pathobiological importance, KMTs have garnered immense attention over the last decade as attractive therapeutic targets. These endeavors have culminated in tens of chemical probes that have been used to interrogate many aspects of histone lysine methylation. Besides, over a dozen inhibitors have been advanced to clinical trials, including the EZH2 inhibitor tazemetostat approved for the treatment of follicular lymphoma and advanced epithelioid sarcoma. In this Review, we highlight the chemical biology and pharmacology of KMT inhibitors and targeted protein degraders focusing on the clinical development of EZH1/2, DOT1L, Menin-MLL, and WDR5-MLL inhibitors. We also briefly discuss the pharmacologic targeting of other KMTs.

Keywords: DOT1L; EZH2; G9a/GLP; Histone Methyltransferase; Menin-MLL; NSD; PRC2; SETD7; SETD8; SUV420H1/2; WDR5-MLL.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Biology
Epigenesis, Genetic
Histones* / metabolism
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Lysine / metabolism
Methylation
Neoplasms* / drug therapy
Neoplasms* / genetics
Protein Processing, Post-Translational

Substances

Histones
Intracellular Signaling Peptides and Proteins
WDR5 protein, human
Lysine