Abstract 1732: Mastering metastases by novel selective CDK9 Inhibitor ORI-15412

Abstract Metastases, the leading cause of cancer-related morbidity and deaths, remain a major therapeutic challenge, highlighting the critical need for novel treatments. Our study evaluates the efficacy of ORI-15412, an oral and fully brain-penetrant CDK9 inhibitor developed by Origenis, designed to meet this need through selective inhibition of CDK9 and modulation of key pathways involved in cancer progression and metastasis. ORI-15412 was engineered using Origenis' proprietary technologies - MOREsystem®, MolMind®, BRAINstorm™, and Cippix® - for optimized blood-brain barrier penetration, selectivity, and potency. By targeting the pTEFb complex and downstream effectors, including phospho-RNA Pol II, MCL-1, and c-Myc, ORI-15412 induces apoptosis and suppresses osteoclast differentiation in cancer models. It also demonstrates dose-dependent reduction in NF-κB-dependent p52 expression, suggesting potential immune modulatory effects. In vivo studies using the aggressive intracardial MV4-11_luc metastatic mouse model showed that ORI-15412 achieved 95% tumor growth inhibition (TGI) and up to 99.99% reduction in metastasis across the brain, bones, bone-marrow, lymph nodes, and lungs. The drug was well-tolerated with no observed toxicity, and efficacy was dose-dependent, underscoring its potential for treating metastatic cancers. Having completed all IND-enabling safety and toxicity studies with NOAEL at efficacious doses, ORI-15412 is positioned as a clinical-ready candidate, offering a promising new approach for patients with metastatic cancers, particularly those with brain and bone involvement. Citation Format: Gergana Galabova, Michael Almstetter, Nicole Brusis, Christiane Gilch, Roland Koestler, Julie Kondrotas, Jan Kubitzki, Henrik Kuhn, Federico Medda, Patricia Perez-Galan, Jean Tassel, Nadine Traube, Andreas Treml, David Wifling, Nasser Yehia, Peter Zegar, Michael Thormann. Mastering metastases by novel selective CDK9 Inhibitor ORI-15412 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1732.