Design, synthesis, and evaluation of quinoxaline-based survivin inhibitors for castration-resistant prostate cancer.

Survivin, a member of the Inhibitors of Apoptosis Protein (IAP) family, is a homodimer and plays a vital role in cell survival and cell cycle progression. Due to its unique expression pattern in nearly all cancers but not normal adult tissues, survivin has been regarded as an ideal anticancer drug target. Targeting its hydrophobic dimerization interface has recently resulted in novel survivin degraders that induce its degradation in the proteasome. One orally available degrader, LQZ-7I (7I), has a quinoxaline core linked to two 4-fluorobenzyl groups via two secondary amine bonds. In this study, we tested the hypothesis that the electron-withdrawing groups (EWGs) on the benzene rings facilitate the binding to survivin and increase cytotoxicity using a reiterative medicinal chemistry approach. This led to the identification of two promising 7I analogs, 7I10 and 7I14, with the same quinoxaline pharmacophore but more or stronger EWGs, 3,4,5-trifluoro and 4-trifluoromethyl groups, respectively. Their cytotoxic IC values are approximately 7-20 folds lower than that of the parent 7I against prostate cancer C4-2 and PC-3 cell lines, consistent with their increased activity in eliminating survivin. Furthermore, ectopic overexpression of survivin conferred resistance to both 7I10 and 7I14, confirming their on-target effects. Finally, 7I14 at 15 mg/kg twice per week, effectively suppressed the growth of the PC-3 xenograft tumors, with a ∼ 54 % tumor growth-inhibition rate and significant survivin downregulation but without apparent toxicity. Thus, we conclude that EWGs on the benzene rings are critical for the activity of these quinoxaline-based survivin inhibitors and that their further development may lead to clinically useful anticancer drugs.