7TY2

Crystal Structure of SETD2 Bound to an Indole-based Inhibitor

7TY2 の概要

• エントリーDOI: 10.2210/pdb7ty2/pdb
• 分子名称: Histone-lysine N-methyltransferase SETD2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• 機能のキーワード: histone-lysine n-methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32950.64

構造登録者

Farrow, N.A. (登録日: 2022-02-11, 公開日: 2022-08-31, 最終更新日: 2024-04-03)

主引用文献

Alford, J.S.,Lampe, J.W.,Brach, D.,Chesworth, R.,Cosmopoulos, K.,Duncan, K.W.,Eckley, S.T.,Kutok, J.L.,Raimondi, A.,Riera, T.V.,Shook, B.,Tang, C.,Totman, J.,Farrow, N.A.
Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies.
Acs Med.Chem.Lett., 13:1137-1143, 2022

PubMed Abstract: SETD2, a lysine -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.

PubMed: 35859865
DOI: 10.1021/acsmedchemlett.2c00167

実験手法

X-RAY DIFFRACTION (2.438 Å)