Abstract A035: The nitroalkene (E)-8-nitrononadec-7-enoic acid (CP-8) is a potent and reversible inhibitor of HR-mediated DNA DSB repair

Abstract Triple-negative breast cancer (TNBC) represents about 20% of all breast cancers. TNBC is highly aggressive, with only 12% of patients diagnosed with advanced disease surviving beyond 5 years. TNBC treatment has been influenced by defects in DNA double-strand breaks (DSB) repair resulting from mutations in BRCA1/2 genes. This has led to establishing a BRCA-like phenotype to predict TNBC's sensitivity to DNA-damaging agents like ionizing radiation, platinum salts, anthracyclines, and inhibitors of Poly (ADP-ribose) polymerase (PARPi). PARPi therapy has revolutionized cancer treatment but is limited by two critical factors: first, most PARPi-treated BRCA1/2-deficient patients develop PARPi resistance due to cancer cells regaining homologous-recombination (HR)-mediated DNA DSB function. Secondly, 80% of all TNBC patients express wild-type BRCA1/2 genes and, thus, are currently not eligible for PARPi therapies. Our drug development program offers a significant option for TNBC patients. Testing 50 synthetic nitroalkenes based on (E)-9/10-nitrooctadec-9-enoic acid, we found the nitroalkene (E)-8-nitrononadec-7-enoic acid (CP-8) to be a potent HR-mediated DNA DSB repair inhibitor that reversibly inhibits the RAD51 recombinase by modifying its cysteine 319. That way, CP-8 induces a BRCAness-like phenotype, effectively killing TNBC cells wild-type for BRCA genes. CP-8 synergizes with DNA-damaging therapies in vitro and in vivo in both TNBC-naïve and PARPi-resistant models. To date, we have completed preclinical development activities on CP-8, including in vitro safety pharmacology, secondary pharmacodynamics, and pharmacokinetics addressing absorption, distribution, metabolism, and solubility. In summary, CP-8 is a valuable new preclinical asset for treating TNBC-naïve and PARPi-resistant models, regardless of their BRCA status. Citation Format: Carola A. Neumann. The nitroalkene (E)-8-nitrononadec-7-enoic acid (CP-8) is a potent and reversible inhibitor of HR-mediated DNA DSB repair [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 A035.