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

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: DC50 = 3.7 nM, Dmax = 90%; AR-V7: DC50 = 3.0 nM, Dmax = 93%; GSPT1: DC50 = 1.2 nM, Dmax = 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.