Abstract LB166: OP-3136, a selective KAT6 inhibitor, demonstrates anti-tumor activity in prostate, ovarian, and non-small cell lung cancer preclinical models

Abstract Histone lysine acetyltransferases KAT6A and KAT6B are frequently dysregulated in cancer and are mechanistically linked to key oncogenic processes. Small-molecule inhibitors of KAT6 have shown promising clinical efficacy, particularly in ER/HER2- metastatic breast cancer. However, KAT6 inhibitors remain largely unexplored in other solid tumors despite strong biological and mechanistic rationale for KAT6 as a potential target. Here, we report for the first time that the inhibition of KAT6 using OP-3136, a highly selective KAT6 inhibitor currently in Phase 1 clinical trials, demonstrates robust anti-tumor activity in preclinical models of prostate cancer, ovarian cancer, and non-small cell lung cancer (NSCLC), both in vitro and in vivo. In vitro proliferation assays were conducted on KAT6A-expressing or overexpressing cell lines: VCAP (prostate cancer), OAW28 (ovarian cancer, KAT6A-amplified), OVCAR3 (ovarian cancer), and LCLC-97TM1 (NSCLC). In vivo efficacy was evaluated in xenograft models using OVCAR3 and LCLC-97TM1 cells in immunocompromised mice.OP-3136 inhibited proliferation across all tested prostate cancer, ovarian cancer and NSCLC cell lines. In the OVCAR3 xenograft ovarian cancer model, oral administration of OP-3136 as monotherapy at 0.5 and 1 mg/kg resulted in tumor regression with tumor growth inhibition (TGI) of 104.5% and 105.4%, respectively. In the LCLC-97TM1 NSCLC xenograft model, monotherapy with OP-3136 at 1 mg/kg achieved a TGI of 62%. These findings highlight the potential of OP-3136 monotherapy to treat prostate, ovarian, and NSCLC tumors and strongly support expanding the clinical investigation of KAT6 inhibitors beyond ER+/HER2- breast cancer. Citation Format: Gopinath S. Palanisamy, Susanna A. Barratt, Chelsea Hope, Srinivasan Jayaraman, Brandon Robello, Guadalupe Peña, Raymond A. Ng, David C. Myles. OP-3136, a selective KAT6 inhibitor, demonstrates anti-tumor activity in prostate, ovarian, and non-small cell lung cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB166.