Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies.
Basic Information
ID: ALA5120931
Journal: ACS Med Chem Lett
Title: Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies.
Authors: Alford JS, Lampe JW, Brach D, Chesworth R, Cosmopoulos K, Duncan KW, Eckley ST, Kutok JL, Raimondi A, Riera TV, Shook B, Tang C, Totman J, Farrow NA.
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.
CiteXplore: 35859865
DOI: 10.1021/acsmedchemlett.2c00167
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