2. Academic Validation
  3. Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

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

  • ACS Med Chem Lett. 2022 Jun 7;13(7):1137-1143. doi: 10.1021/acsmedchemlett.2c00167.
Joshua S Alford 1,  John W Lampe 1,  Dorothy Brach 1,  Richard Chesworth 1,  Kat Cosmopoulos 1,  Kenneth W Duncan 1,  Sean T Eckley 1,  Jeffrey L Kutok 1,  Alejandra Raimondi 1,  Thomas V Riera 1,  Brian Shook 1,  Cuyue Tang 1,  Jennifer Totman 1,  Neil A Farrow 1
Affiliations

Affiliation

  • 1 Epizyme Inc., 50 Hampshire Street, Sixth Floor, Cambridge, Massachusetts 02139, United States.
PMID: 35859865 DOI: 10.1021/acsmedchemlett.2c00167
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.

Figures
Products