Abstract 3024: The novel selective CDK9 Inhibitor ORI-15412 reduces PD-L1 expression and drives the efficacy in combination therapies for melanoma and triple-negative breast cancer

Aggressive cancers like melanoma and triple-negative breast cancer (TNBC) are challenging to treat due to limited therapeutic options and high relapse rates. Advances in combination therapies offer promise by targeting multiple cancer progression and resistance pathways. This study explores ORI-15412, Origenis' novel, oral CDK9 inhibitor, as monotherapy and in combination therapies in syngeneic melanoma (B16F10) and TNBC (4T1) murine models. ORI-15412, developed with Origenis' proprietary MOREsystem®, MolMind®, BRAINstorm™, and Cippix® technologies, shows unhindered brain penetration, high selectivity, and potency. Its CDK9 inhibition effectively targets the pTEFb complex and downstream pathways, including phospho-RNA Pol II, MCL-1, and c-MYC, inducing apoptosis and inhibiting osteoclast differentiation in cancer cell models (L363, MV4-11, and huPBMCs). ORI-15412 also dose-dependently reduces PD-L1 expression, highlighting its potential to modulate immune responses. In vivo, ORI-15412 monotherapy showed significant tumor growth inhibition (TGI) in B16F10 melanoma and 4T1 TNBC models. Combined with anti-PD-1 antibody, Vemurafenib, or Trametinib, it enhanced anti-tumor activity, achieving 72-84% TGI in the B16F10 model. In the 4T1 TNBC model, combining ORI-15412 with anti-PD-1 antibody achieved a 63% TGI, outperforming monotherapies or controls. ORI-15412 was non-toxic at effective doses in mono and combination therapies. These findings highlight ORI-15412 as a pivotal component in combination therapy for hard-to-treat cancers. Its effects on tumor growth inhibition and immune checkpoint modulation support its selection as a clinical candidate for melanoma, TNBC, and other malignancies. Citation Format: Gergana Galabova, Michael Almstetter, Nicole Brusis, Christiane Gilch, Roland Koestler, Julie Kondrotas, Jan Kubitzki, Henrik Kuhn, Hendrik Liebers, Federico Medda, Patricia Perez-Galan, Jean Tassel, Nadine Traube, Andreas Treml, David Wifling, Nasser Yehia, Peter Zegar, Michael Thormann. The novel selective CDK9 Inhibitor ORI-15412 reduces PD-L1 expression and drives the efficacy in combination therapies for melanoma and triple-negative breast cancer [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 3024.