9MFT

Human DHX9 in Complex with ATX968 and ADP

これはPDB形式変換不可エントリーです。

9MFT の概要

• エントリーDOI: 10.2210/pdb9mft/pdb
• 分子名称: ATP-dependent RNA helicase A, (4M)-N-[3-chloro-5-(methanesulfonamido)phenyl]-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, ADENOSINE-5'-DIPHOSPHATE, ... (7 entities in total)
• 機能のキーワード: helicase, dhx9, inhibitor, complex, hydrolase
• 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: 115721.98

構造登録者

Lockbaum, G.J.,Lee, Y.-T.,Sickmier, E.A.,Boriack-Sjodin, P.A.,Grigoriu, S. (登録日: 2024-12-10, 公開日: 2025-05-07, 最終更新日: 2025-05-21)

主引用文献

Daniels, M.H.,Castro, J.,Lee, Y.T.,Gotur, D.,Knockenhauer, K.E.,Grigoriu, S.,Lockbaum, G.J.,Cheong, J.E.,Lu, C.,Brennan, D.,Buker, S.M.,Liu, J.,Yao, S.,Sparling, B.A.,Sickmier, E.A.,Ribich, S.,Blakemore, S.J.,Silver, S.J.,Boriack-Sjodin, P.A.,Duncan, K.W.,Copeland, R.A.
Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.
J.Med.Chem., 68:9537-9554, 2025

PubMed Abstract: DHX9 is an RNA/DNA helicase integral in the maintenance of genome stability that has emerged as an attractive target for oncology drug discovery. Disclosed herein is the discovery and optimization of a series of DHX9 inhibitors. Compound was identified as a partial inhibitor of DHX9 ATPase activity but a full inhibitor of unwinding activity. Binding of to a pocket distinct from the ATP binding site was confirmed by X-ray crystallography, enabling structure-based drug optimization. During this optimization, a sulfur-halogen bond was identified that increased on-target residence time without impacting equilibrium binding affinity. Analysis shows that cell potency more closely correlates with residence time than with equilibrium measurements of binding affinity or biochemical potency. Further optimization of potency and ADME properties led to the identification of , a potent and selective DHX9 inhibitor that is efficacious in a tumor xenograft model of microsatellite instability-high (MSI-H) colorectal cancer.

PubMed: 40298172
DOI: 10.1021/acs.jmedchem.5c00252

実験手法

X-RAY DIFFRACTION (2.75 Å)