Abstract 6907: Novel TACC3 protein-protein interaction inhibitor, AO-252, shows potent activity in prostate, gastric cancers, and triple negative breast cancer with brain metastasis

Abstract TACC3 (Transforming Acidic Coiled-Coil-Containing 3) is a key player in microtubule and centrosomal processes and is considered to have an important role in causing chromosomal instability, leading to aggressive cancer. TACC3 overexpression is found in multiple cancers and strongly associated with a poor prognosis in those cancer types. TACC3 is a pleiotropic gene which binds to multiple proteins and plays an important role in DNA damage response mechanisms, hematopoiesis, epigenetics, and immune functions. While TACC3 is essential for cancer cells but it is dispensable for normal cells based on conditional knockout in adult mice, making it an ideal treatment target for highly aggressive cancers. We had previously shown that AO-252, a novel small molecule TACC3 protein-protein interaction (PPI) inhibitor, exhibited strong in vivo efficacy in triple negative breast cancer (TNBC) and ovarian cancer. In the present work, we show in vitro and vivo assays that AO-252 shows exceptional efficacy in prostate, gastric cancers and TNBC with brain metastases. In all these cancers, AO-252 exhibited dose dependence on tumor growth inhibition and complete responses in xenograft models. In addition, these responses demonstrated to be durable even after stopping the treatment with AO-252. We also show that AO-252 exerts its activity by destabilizing the C-terminus of TACC3 and disrupting the protein-protein interactions occurring in the C-terminus (EGFR, NOTCH, BRCA1, HIF1b/ARNT, KIFC1, HDAC2, MBD2, DNAPK etc) without blocking the N-terminus interactions. AO-252 is currently in first-in-human (FIH), Phase I clinical trial in TNBC, ovarian and endometrial cancers (NCT06136884). We are in the process of expanding our trial to include prostate, gastric cancer and TNBC with brain metastases. Citation Format: Sridhar Vempati, Chaemin Lim, Robbin Frnka, Edward Painter, Sotirios G. Stergiopoulos. Novel TACC3 protein-protein interaction inhibitor, AO-252, shows potent activity in prostate, gastric cancers, and triple negative breast cancer with brain metastasis [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 6907.