Novel quinoxaline-based survivin degraders overcome docetaxel-resistance in castration-resistant prostate cancer

Survivin, a homodimeric protein in the inhibitor of apoptosis protein (IAP) family, plays a dual role in apoptosis inhibition and cell cycle regulation. Overexpressed in many cancers but absent in most adult tissues, survivin is a compelling therapeutic target linked to disease progression, aggressiveness, and drug resistance. However, its structural properties render it “undruggable” by conventional approaches. Here, we present a transformative strategy to overcome this challenge by targeting survivin’s hydrophobic dimerization interface, inducing proteasome-dependent degradation. Building on the initial discovery of the survivin degrader LQZ-7I, we developed optimized analogs with significantly enhanced potency through medicinal chemistry. Our top-performing compounds, 7I10 and 7I14, selectively disrupt survivin dimerization, leading to its degradation and spontaneous apoptosis in castration-resistant prostate cancer (CRPC) cells. We also show that survivin contributes to acquired resistance to docetaxel, the frontline chemotherapy for metastatic CRPC, and that the survivin degraders exhibit potent synergy with docetaxel and the combination of 7I14 and docetaxel synergistically eliminates CRPC xenografts without added toxicity. This work introduces a first-in-class therapeutic approach that overcomes long-standing barriers to drugging survivin, offering a new avenue for combating the docetaxel resistant metastatic CRPC. With robust efficacy, a favorable safety profile, and potential for clinical translation, 7I10 and 7I14 represent significant advancements in the development of targeted cancer therapies to overcome docetaxel resistance. • Survivin contributes to acquired docetaxel resistance in castration-resistant prostate cancer (CRPC) cells. • Small molecule lead inhibitors LQZ-7I10 and LQZ-7I14 disrupt survivin dimerization, leading to proteasome-dependent survivin degradation, and spontaneous apoptosis of CRPC cells. • LQZ-7I10 and LQZ-7I14 synergize with docetaxel and overcome acquired docetaxel resistance in CRPC cells. • LQZ-7I14 induces survivin loss and apoptosis in xenograft CRPC tumors and synergize with docetaxel in vivo.