Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

Abstract

SETD2, a lysine N -methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.

Virtual Special Issue: Epigenetics 2022

“…Farrow and co-workers report on EZM0141, a potent selective inhibitor of SETD2 which is in Phase I clinical trials for cancer. 25 The development of brain penetrant EZH2 (enhancer of zeste homologue 2) inhibitors for cancers is reported by Liang, Phillips, and co-workers. 26 Also focusing on brain cancers, and in particular neuroblastoma, Dev et al describe a formulation strategy that delivers a pool of acetate together with a chemotherapeutic agent with the goal of rebalancing the aberrant methylation/ acetylation state of cancer cells.…”

“…As part of this joint virtual special issue, we continue this trend. Farrow and co-workers report on EZM0141, a potent selective inhibitor of SETD2 which is in Phase I clinical trials for cancer . The development of brain penetrant EZH2 (enhancer of zeste homologue 2) inhibitors for cancers is reported by Liang, Phillips, and co-workers .…”

Microtubule‐associated proteins and enzymes modifying tubulin

“…Since some of the enzymes modify not only MT but also other substrates, drugs acting on enzymes that mediate PTMs of MT would also alter the functions of other proteins (Alford et al, 2022; Patra, Praharaj, Klionsky, & Bhutia, 2022). For example, vorinostat binds to the catalytic domain of the histone deacetylases (HDACs) to inhibit deacetylation MT.…”

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

“…These results indicate that expression regulation or enzymatic inhibition of SETD2 is potential drug targets for prostate cancer. SETD2-selective inhibitors (EPZ-719, 95 compound C13, 96 and EZM0414 97 ) have been reported. Among them, compound C13 inhibits the proliferation of leukemia cell lines 96 and EZM0414 inhibits the proliferation of multiple myeloma cells in xenograft model mice.…”

“…Among them, compound C13 inhibits the proliferation of leukemia cell lines 96 and EZM0414 inhibits the proliferation of multiple myeloma cells in xenograft model mice. 97 Thus, these compounds may be a useful drug for prostate cancer, although EZH2 expression levels may be altered.…”