A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair.

ABSTRACT: DHX9 is a multifunctional DExH-box RNA helicase with important roles in the regulation of transcription, translation, and maintenance of genome stability. Elevated expression of DHX9 is evident in multiple cancer types, including colorectal cancer. Microsatellite instable-high (MSI-H) tumors with deficient mismatch repair (dMMR) display a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. In this report, we show that DHX9 knockdown increased RNA/DNA secondary structures and replication stress, resulting in cell-cycle arrest and the onset of apoptosis in cancer cells with MSI-H/dMMR. ATX968 was identified as a potent and selective inhibitor of DHX9 helicase activity. Chemical inhibition of DHX9 enzymatic activity elicited similar selective effe

SUBMITTER: Castro J 

PROVIDER: S-EPMC11831107 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature