9mfo
Human DHX9 in Complex with Compound 1 and ADP
Structural highlights
FunctionDHX9_HUMAN Unwinds double-stranded DNA and RNA in a 3' to 5' direction. Alteration of secondary structure may subsequently influence interactions with proteins or other nucleic acids. Functions as a transcriptional activator. Component of the CRD-mediated complex that promotes MYC mRNA stability. Involved with LARP6 in the stabilization of type I collagen mRNAs for CO1A1 and CO1A2. As component of a large PER complex is involved in the inhibition of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms. Positively regulates HIV-1 LTR-directed gene expression.[1] [2] [3] Publication Abstract from PubMedDHX9 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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