Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders

Abstract

PROTAC and molecular glue present a novel therapeutic approach to tackle diseases propelled by the aberrant expression of disease-causing proteins. In this study, we identified a number of AR/AR-V7 and GSPT1 degraders that possess both PROTAC and molecular glue characteristics. The exploration of SAR led to the discovery of BWA-6047 as a potent degrader. BWA-6047 exhibited potent protein degradation in 22Rv1 cells (AR: DC 50 = 3.7 nM, D max = 90%; AR-V7: DC 50 = 3.0 nM, D max = 93%; GSPT1: DC 50 = 1.2 nM, D max = 94%). Mechanism experiments indicate that BWA-6047 functions as both PROTAC and molecular glue to degrade target proteins. Oral administration of BWA-6047 at 20 mpk significantly inhibited LNCaP xenograft tumor growth in mice without obvious toxicity. Dual AR/AR-V7 and GSPT1 degraders represent a class of promising novel mechanism compounds for further extensive evaluations in prostate cancer treatment.