Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.

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 1 was identified as a partial inhibitor of DHX9 ATPase activity but a full inhibitor of unwinding activity. Binding of 1 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 biochemica

SUBMITTER: Daniels MH 

PROVIDER: S-EPMC12067447 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature