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

被引：23

作者：

Alford, Joshua S. ^{[1
]}

Lampe, John W. ^{[1
]}

Brach, Dorothy ^{[1
]}

Chesworth, Richard ^{[1
]}

Cosmopoulos, Kat ^{[1
]}

Duncan, Kenneth W. ^{[1
,2
]}

Eckley, Sean T. ^{[1
]}

Raimondi, Alejandra ^{[1
]}

V. Riera, Thomas ^{[1
]}

Shook, Brian ^{[1
]}

Tang, Cuyue ^{[1
,3
]}

Totman, Jennifer ^{[1
]}

Farrow, Neil A. ^{[1
]}

机构：

[1] Epizyme Inc, Cambridge, MA 02139 USA

[2] Accent Therapeut, 65 Hayden Ave, Lexington, MA 02421 USA

[3] Remix Therapeut, One Kendall Sq,Bldg 200, Cambridge, MA 02139 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2022年 / 13卷 / 07期

关键词：

Histone methyltransferase; SETD2; HISTONE H3; IDENTIFICATION; TARGETS;

D O I：

10.1021/acsmedchemlett.2c00167

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1137 / 1143

页数：7

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