Abstract 5651: Discovery of AS03157 as a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs)

Abstract Background: Overexpression of antiapoptotic proteins, such as cellular inhibitor of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) and X-linked IAP (XIAP), occurs in various hematologic and solid cancers and is associated with drug resistance and poor prognosis. Several small molecules are being investigated clinically as monotherapy or in combination therapy in solid tumors. AS03157, a novel and structurally distinct IAP antagonist, was identified with enhanced specificity towards cIAP1 and XIAP, and its pharmacological profiles were characterized in vitro and in vivo. Methods: Homogeneous time-resolved fluorescence assays were used to measure the binding of the compound to its target. Detroit 562 cell line was used to test the target degradation. MDA-MB-231 and EVSA-T breast cancer cell lines were used for antiproliferation assay. In vivo efficacy was evaluated in MDA-MB-231-derived xenograft model. Results: AS03157 strongly bound to cIAP1-BIR3 and XIAP-BIR3 at half-maximal inhibitory concentration (IC50) values of 4.3 nM and 13.7 nM, respectively. AS03157 inhibited cIAP1 with a half-maximal degradation concentration (DC50) of 1.38 nM after treatment for 2 hours in a Detroit 562 pharyngeal carcinoma cell line in vitro. AS03157 demonstrated potent growth inhibitory activities in MDA-MB-231 and EVSA-T breast cancer cell lines, with IC50 values of 20 nM and 2 nM, respectively. In addition, AS03157 exhibited high aqueous solubility, metabolic stability, as well as high oral bioavailability in both rodent and non-rodent species. Of interest, AS03157 10 and 20 mg/kg administered orally daily demonstrated dose-dependent antitumor activity in an MDA-MB-231-X1 human breast cancer xenograft model, with T/C values of 69.81% and 26.67% on Day 22, respectively. Conclusions: AS03157 showed promising in vitro and in vivo activity in preclinical cancer models, and these data provide a rationale for further clinical studies. Citation Format: Yan Xiong, Zhou Yu, Jiantao Hu, Jianyong Chen, Xiao Han, Zhiyan Liang, Yifan Zhai, Dajun Yang. Discovery of AS03157 as a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs) [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 5651.