Discovery of a Highly Potent PROTAC Degrader of p300/CBP Proteins for the Treatment of Enzalutamide-Resistant Prostate Cancer

Prostate cancer therapies against androgen receptor (AR)
eventually
develop lethal resistance; thus, exploring new therapeutic approaches
is urgent for prostate cancer treatment. Acetyltransferase p300/CBP
are key coactivators for AR-mediated transcription and represent promising
therapeutic targets to inhibit AR activity in prostate cancer. We
describe the design synthesis and evaluation of a new class of p300/CBP
PROTAC degraders. We identified an excellent p300/CBP degrader MJP6412, which effectively induced degradation of p300/CBP
proteins, downregulated AR target genes, and inhibited cell growth
of human prostate cancer cell lines and enzalutamide-resistant cells
with IC50 even at nanomolar concentrations. Furthermore, MJP6412 demonstrated significant inhibition of tumor growth
in a VCaP xenograft model. Collectively, MJP6412 is a
promising lead compound for the treatment of prostate cancer, especially
enzalutamide-resistant prostate cancer.