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

  • J Med Chem. 2024 Sep 29. doi: 10.1021/acs.jmedchem.4c01100.
Mengjun Ma  1 ,  Mengyao Li  1 ,  Chengwei Zhang  1 ,  Zixuan Yang  1 ,  Xiaoyu Chen  1 ,  Penghui Lu  1 ,  Shuangshuang Nie  1 ,  Siqi Zhang  1  2 ,  Shumin Ma  1  2 ,  Chong Qin  1  2  3
Affiliations
  • 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, Shandong, China.
  • 2. Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao 266003, Shandong, China.
  • 3. Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, Shandong, China.
PMID: 39344125 DOI: 10.1021/acs.jmedchem.4c01100
Abstract

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.

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