Abstract 1664: Survivin degrader 7I14 synergizes with docetaxel in castration-resistant prostate cancer by disrupting survivin dimerization and inducing its proteasome-dependent degradation

Abstract Survivin, the smallest member of the Inhibitor of Apoptosis Protein (IAP) family, forms homodimers and coordinates with other IAPs to inhibit apoptosis by suppressing pro-apoptotic caspase 3/9 activation, contributing to drug resistance. Due to its overexpression in cancer cells and lack of expression in normal adult tissues, survivin is an attractive cancer target. However, developing survivin-selective inhibitors has been challenging due to the absence of suitable active sites for targeting. Strategies have been pursued to inhibit survivin expression by targeting its upstream transcriptional regulators, notably leading to discovery of YM155, which unexpectedly suffers from poor pharmacokinetics and multiple targets, including the ubiquitous transcription factor Sp1. We recently developed a novel approach to directly target survivin for discovery of survivin degraders by disrupting its dimerization, exposing the hydrophobic interface, and promoting proteasome-mediated degradation. The compound 7I, a quinoxaline-based survivin degrader, likely interacts with key residues for survivin dimerization via π-π interactions. We hypothesized that electron-withdrawing groups on 7I enhance its binding to survivin. To test this hypothesis, we synthesized a series of 7I analogs and identified two improved leads, 7I10 and 7I14, with up to 20-fold greater activity, selectively degrading survivin in castration-resistant prostate cancer (CRPC) cell lines C4-2 and PC-3. Both 7I10 and 7I14 dose-dependently induced spontaneous apoptosis and synergized with docetaxel, a first-line therapy for metastatic CRPC. In a PC-3 xenograft model, 7I14 at 15 mg/kg administered via IP twice/week effectively suppressed tumor growth and enhanced docetaxel’s effects by degrading survivin, with no added toxicity, as assessed by body weight, white blood cell counts, and hemoglobin levels. Thus, targeting survivin's dimerization domain is a promising strategy for its degradation, and 7I10 and 7I14 have potential as single agents or in combination with docetaxel for treating metastatic CRPC. Citation Format: Qingbin Cui, Caoqinglong Huang, Xunzhen Zheng, Zizheng Dong, Jing-Yuan Liu, Jian-Ting Zhang. Survivin degrader 7I14 synergizes with docetaxel in castration-resistant prostate cancer by disrupting survivin dimerization and inducing its proteasome-dependent degradation [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 1664.