9mfp

Cat DHX9 in Complex with Compound 1 and ADP

spinqualitylabelsall models 9mfp, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mfp is a 1 chain structure with sequence from Felis catus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.27Å Ligands: A1BK0, ADP, EDO, MG, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function M3WPI7_FELCA Publication Abstract from PubMed 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. Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.,Daniels MH, Castro J, Lee YT, Gotur D, Knockenhauer KE, Grigoriu S, Lockbaum GJ, Cheong JE, Lu C, Brennan D, Buker SM, Liu J, Yao S, Sparling BA, Sickmier EA, Ribich S, Blakemore SJ, Silver SJ, Boriack-Sjodin PA, Duncan KW, Copeland RA J Med Chem. 2025 Apr 29. doi: 10.1021/acs.jmedchem.5c00252. PMID:40298172 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA