7ty3 | pdb_00007ty3
Crystal Structure of SETD2 Bound to an Indole-based Inhibitor
Structural highlights
Function[SETD2_HUMAN] Histone methyltransferase that methylates 'Lys-36' of histone H3. H3 'Lys-36' methylation represents a specific tag for epigenetic transcriptional activation. Probably plays a role in chromatin structure modulation during elongation via its interaction with hyperphosphorylated POLR2A. Binds DNA at promoters. May also act as a transcription activator that binds to promoters. Binds to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.[1] Publication Abstract from PubMedSETD2, 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. Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies.,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 ACS Med Chem Lett. 2022 Jun 7;13(7):1137-1143. doi:, 10.1021/acsmedchemlett.2c00167. eCollection 2022 Jul 14. PMID:35859865[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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