Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer

  • J Med Chem. 2023 Aug 24;66(16):11158-11186. doi: 10.1021/acs.jmedchem.3c00585.
Bowen Zhang  1 ,  Chang Liu  1 ,  Zhenqian Yang  1 ,  Sai Zhang  1  2 ,  Xiaolin Hu  1 ,  Baohu Li  1 ,  Mei Mao  1 ,  Xiao Wang  1  2 ,  Zhuoyue Li  1  2 ,  Shumin Ma  1  2 ,  Siqi Zhang  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, Shandong 266003, China.
  • 2. Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 3. Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong 266137, China.
PMID: 37556600 DOI: 10.1021/acs.jmedchem.3c00585
Abstract

We report small molecular PROTAC compounds targeting the Androgen Receptor N-terminal domain (AR-NTD), which were obtained by tethering AR-NTD antagonists and different classes of E3 Ligase ligands through chemical linkers. A representative compound, BWA-522, effectively induces degradation of both AR-FL and AR-V7 and is more potent than the corresponding antagonist against prostate Cancer (PC) cells in vitro. We have shown that the degradation of AR-FL and AR-V7 proteins by BWA-522 can suppress the expression of AR downstream proteins and induce PC cell Apoptosis. BWA-522 achieves 40.5% oral bioavailability in mice and 69.3% in beagle dogs. In a LNCaP xenograft model study, BWA-522 was also proved to be an efficacious PROTAC degrader, resulting in 76% tumor growth inhibition after oral administration of a dose of 60 mg/kg. This study indicates that BWA-522 is a promising AR-NTD PROTAC for the treatment of AR-FL- and AR-V7-dependent tumors.

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