Recent progress in developing selective inhibitors of protein methyltransferases

Abstract

Mounting evidence suggests that protein methyltrans•ferases (PMTs), which catalyze methylation of histone as well as non-histone •proteins, play aa crucial role in diverse biological pathways and human• diseases. In particular, PMTs have been recognized as major players in •regulating gene expression and chromatin state. There has been an increasingly growing• interest in these enzymes as potential therapeutic targets and over the past two years tremendous progress has been made in the discovery of selective, small molecule inhibitors of protein lysine and arginine methyltransferases. Inhibitors of PMTs have been used extensively in oncology studies as tool compounds, and inhibitors of EZH2, DOT1L and PRMT5 are currently in clinical trials.

Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers

“…To better assess the therapeutic relevance of PRMT5 targeting in TNBC, we next examined the effect of PRMT5 inhibition on a panel of breast cell lines using the PRMT5specific inhibitor EPZ015666. 13,14,27 First, we confirmed that EPZ015666 inhibits PRMT5 activity by analyzing PRMT5specific methylation marks on histones H3 (H3R8me2s) and H4 (H4R3me2s) ( Figure 3A; Figure S5). We then conducted a cell viability assay on 13 breast cell lines, comprising eight TNBC-derived cell lines (ER-/PR-/HER-) from the different TNBC molecular subtypes defined by Lehmann 2 (Table S3), but also one ER+ (MCF-7), two ER−/HER2+ (HCC1954, SKBR3), and two non-tumorigenic mammary cell lines (MCF-10A, MCF-12A), for comparison purposes.…”

“…Despite considerable improvement in breast cancer therapeutic management, no targeted therapy yet exists for the treatment of TNBC, and this breast cancer subtype remains a challenge for oncologists. PRMTs have recently received considerable attention as potential therapeutic targets in various types of cancer, and several specific PRMT inhibitors have recently been described . The present study suggests a promising therapeutic potential for PRMT5 targeting in a subset of TNBC, using the small‐molecule inhibitor EPZ015666 .…”

“…14 The present study suggests a promising therapeutic potential for PRMT5 targeting in a subset of TNBC, using the small-molecule inhibitor EPZ015666. 13,14,27 Indeed, we show that PRMT5 inhibition (a) impairs breast cancer cell viability, (b) triggers apoptosis, (c) impedes colony formation (d) affects CSC properties, and (e) slows tumor growth in a TNBC patient-derived xenograft model (PDX). In doing so, we align with previous studies which underline the potential value of PRMT5 inhibition as a therapeutic approach in glioblastoma 32,33 and mantle cell lymphoma.…”

“…[10][11][12] Given this, PRMT5 has been attributed oncogenic functions and has recently received considerable attention as a potential therapeutic target in cancer. Several selective and potent small-molecule inhibitors have been developed against PRMT5 and their effects on cancer development are now being assessed in vitro, in vivo, [13][14][15] as well as in a clinical trial. 15,16 Among these is the inhibitor EPZ015666, which competes with the PRMT5 peptide substrate binding pocket to impede PRMT5-substrate interaction and subsequent methylation.…”

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

“…Epigenetic drug development targeting PRMTs is focused on the reversibility of epigenomic modifications through targeted inhibition of PRMT enzymes. Fortunately, there are sufficient structural distinctions that tolerates and enables selective targeting of PRMTs (Richon et al 2011) using small-molecule inhibitors, creating desirable targets for therapeutic exploitation (Kaniskan & Jin 2017, Copeland 2018. Moreover, the potential translational outcomes associated with the tractable PRMT family are underscored by the list of epigenetic enzyme inhibitors undergoing appraisal in pre-clinical and clinical trials as novel cancer therapies (Hamamoto & Nakamura 2016, Oh et al 2017.…”