Download MendeleyDiscovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.
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.(2025) J Med Chem
- PubMed: 40298172
- DOI: https://doi.org/10.1021/acs.jmedchem.5c00252
- Primary Citation of Related Structures:
9MFO, 9MFP, 9MFQ, 9MFR, 9MFS, 9MFT - 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 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 biochemical potency. Further optimization of potency and ADME properties led to the identification of ATX968 , a potent and selective DHX9 inhibitor that is efficacious in a tumor xenograft model of microsatellite instability-high (MSI-H) colorectal cancer.
Organizational Affiliation:
Accent Therapeutics, Inc., 1050 Waltham Street, Lexington, Massachusetts 02421, United States.
