Abstract B053: Discovery of an allosteric, potent and selective DHX9 helicase inhibitor with best-in-class potential for the treatment of genomically unstable cancers

Abstract Genomic instability and high replication stress are hallmarks of multiple cancer types and offer a unique therapeutic vulnerability. Specifically, microsatellite instability-high (MSI-H) tumors exhibit a strong dependency on DHX9, an RNA helicase critical for genome maintenance and stress responses. Genetic silencing and phenotype rescue assays in MSI-H cancers show a strong dependency on the helicase activity of DHX9, making it an attractive, tumor-selective target. We present a potent, selective, orally bioavailable and brain-penetrant DHX9 helicase inhibitor, with best-in-class potential, for treating MSI-H and other genomically unstable cancers. STM11315 acts via allosteric inhibition and demonstrates high potency and selectivity in biochemical and cellular assays including DHX9-dependent RNA unwinding (IC50 <5 nM) and ATP-ase activity (IC50 <10 nM), with no effect (up to 30 uM) on 10 other helicases. Mechanistically, STM11315 induces replication stress, cell cycle arrest and apoptosis, leading to selective cell killing in MSI-H tumor cells (<20 nM in LS411N vs >10 uM in SW480 in a cell proliferation assay). STM11315 demonstrates robust single-agent efficacy in multiple MSI-H and other genomically unstable in vitro models, including colorectal, endometrial, and ovarian cancer cell lines. In vivo, STM11315 shows compelling single agent anti-tumor activity, achieving complete and durable tumor regression. The compound also induces dose-dependent induction of pharmacodynamic markers of target engagement and response, correlating with efficacy. Pharmacokinetic profiling confirms oral bioavailability, dose-linear plasma and brain exposure, and strong tumor penetration. Human dose predictions suggest daily oral dosing will give sustained 24h target coverage. In summary, our data support DHX9 inhibition as a promising therapeutic strategy for MSI-H and other molecularly defined genomically unstable cancers, addressing a significant unmet need with precision-targeted therapy. The selective mechanism, strong efficacy, favorable PK, and in vitro safety profile support progression of STM11315 into clinical development. Citation Format: Taran Khanam, Helen Harrison, Peter Astles, Elizabeth Anderson, Harry Wing, Angela Shibu, Giles Pergl-Wilson, Rita Chaouni, Richard Fosbeary, Tamsin Samuels, Natalie Webster, Roxine Staats, Beth Thomas, Oliver Rausch. Discovery of an allosteric, potent and selective DHX9 helicase inhibitor with best-in-class potential for the treatment of genomically unstable cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B053.