Summary for 9MFT
| Entry DOI | 10.2210/pdb9mft/pdb |
| Descriptor | 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) |
| Functional Keywords | helicase, dhx9, inhibitor, complex, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 115721.98 |
| Authors | Lockbaum, G.J.,Lee, Y.-T.,Sickmier, E.A.,Boriack-Sjodin, P.A.,Grigoriu, S. (deposition date: 2024-12-10, release date: 2025-05-07, Last modification date: 2025-05-21) |
| Primary citation | 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 Cited by 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: 40298172DOI: 10.1021/acs.jmedchem.5c00252 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.75 Å) |
Structure validation
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