Abstract 1664: Discovery of a novel and potent TACC3 protein-protein interaction inhibitor targeting highly aggressive cancers

Abstract TACC3 is one of the most oncogenic members of the Transforming Acidic Coiled-Coil Containing (TACC) protein family highly overexpressed in multiple different cancers leading to worse prognosis. TACC3 is a key player in microtubule and centrosomal processes and is considered to have an important role in causing chromosomal instability leading to aggressive cancers. TACC3 also plays important role in DNA damage response mechanisms, hematopoiesis, epigenetics and immune functions by interacting with different protein partners. Inhibition of TACC3 by genomic approaches has shown significant reduction in growth of cancer cells in vitro and in vivo. Given its multiple roles in cancer, TACC3 is an ideal therapeutic target for highly aggressive cancers. Here, using phenotypic screening and rational drug design, we developed AO-252, a novel small molecule TACC3 protein-protein interaction (PPI) inhibitor. Binding assays and kinome screening suggested the specificity of AO-252 to TACC3. AO-252 targets the interactions of TACC3 with its known protein partners e.g., Clathrin/KIFC1, BARD1 and MBD2/HAT complexes regulating mitosis, DNA damage response and epigenetic functions. Gene expression profiling in multiple cell lines further confirmed the various TACC3 pathways affected by AO-252. AO-252 showed low nanomolar potency in >200 cell line panel covering various cancer indications and spared the normal cells. AO-252 showed excellent oral pharmacokinetics and demonstrated strong tumor growth inhibition or regression in multiple xenograft models without any safety concerns. Currently, AO-252 is prepared for IND submission for Q1 2023 and will enter clinic in the first half of 2023 for the treatment of advanced solid tumors including triple-negative breast cancer (TNBC), high-grade serous ovarian carcinoma (HGSOC), and endometrial cancer. Citation Format: Ozgur Sahin, Erden Banoglu, Chaemin Lim, Burcu Caliskan, Emmanuel Cruz, Sotirios Stergiopoulos, Sridhar Vempati. Discovery of a novel and potent TACC3 protein-protein interaction inhibitor targeting highly aggressive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1664.