Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer

Abstract

The androgen/androgen receptor (AR) signaling pathway plays an important role in castration-resistant prostate cancer (CRPC). Bifunctional agents that simultaneously degrade AR and inhibit androgen synthesis are expected to block the androgen/AR signaling pathway more thoroughly, demonstrating the promising therapeutic potential for CRPC, even enzalutamideresistant CRPC. Herein, a series of steroid analogs were designed, synthesized, and identified as selective AR degraders, among which YXG-158 (23-h) was the most potent antitumor compound with dual functions of AR degradation and CYP17A1 inhibition. In addition, 23-h abrogated the hERG inhibition and exhibited excellent PK profiles. In vivo, 23-h effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited robust antitumor efficacy both in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant (C4-2b-ENZ) xenograft models. Thus, 23-h was chosen as a preclinical candidate for the treatment of enzalutamide-resistant prostate cancer.

Structure–Activity Relationship (SAR) Studies of Novel Monovalent AR/AR-V7 Dual Degraders with Potent Efficacy against Advanced Prostate Cancer

“…Consequently, Galeterone was terminated in phase III due to unsatisfactory efficacy for AR-V7-positive mCRPC . Subsequent modifications by different groups have resulted in the generation of several steroidal AR/AR-V7 degraders with improved activity and metabolic stability. , However, given the fact that steroidal ligands have the potential to cross-react with other nuclear hormone receptors, off-target effects should be rigorously considered during further development of Galeterone derivatives. Previously, Miller’s group reported the identification of a series of orally bioavailable nonsteroidal AR/AR-V7 degraders by replacing steroid core with an aryl propanamide moiety found in bicalutamide ( 1 ) (Figure ), which showed unprecedented potency against various enzalutamide-resistant cells in vitro and in vivo. − Representative compound UT-34 ( 6 ) (Figure ), albeit derived from the LBD-targeted antagonist bicalutamide, could bind to the AR N-terminal domain (NTD).…”