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 <b>MJP6412</b>, 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 IC<sub>50</sub> even at nanomolar concentrations. Furthermore, <b>MJP6412</b> demonstrated significant inhibition of tumor growth in a VCaP xenograft model. Collectively, <b>MJP6412</b> is a promising lead compound for the treatment of prostate cancer, especially enzalutamide-resistant prostate cancer.
Authors
- Shumin Ma (ORCID: https://orcid.org/0000-0001-6361-9706)
- Chong Qin (ORCID: https://orcid.org/0000-0001-8108-1698)
- Mengyao Li (ORCID: https://orcid.org/0000-0003-0739-4236)
- Xiaoyu Chen (ORCID: https://orcid.org/0000-0002-2521-799X)
- Siqi Zhang (ORCID: https://orcid.org/0000-0001-8682-1683)
- Chengwei Zhang (ORCID: https://orcid.org/0000-0003-1620-4510)
- Penghui Lu
- Zixuan Yang (ORCID: https://orcid.org/0009-0003-0008-7863)
- Mengjun Ma (ORCID: https://orcid.org/0009-0008-2273-065X)
- Shuangshuang Nie
Institutions
- Qingdao National Laboratory for Marine Science and Technology (CN)
- Ocean University of China (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01100
- Citations
- 11
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- Taishan Scholar Project of Shandong Province
- Key Technology Research and Development Program of Shandong
- Natural Science Fund for Distinguished Young Scholars of Shandong Province