Discovery of CW-3308 as a Potent, Selective, and Orally Efficacious PROTAC Degrader of BRD9

  • J Med Chem. 2024 Aug 22;67(16):14125-14154. doi: 10.1021/acs.jmedchem.4c00971.
Changwei Wang  1 ,  Mi Wang  1 ,  Yu Wang  1 ,  Rohan Kalyan Rej  1 ,  Angelo Aguilar  1 ,  Tianfeng Xu  1 ,  Longchuan Bai  1 ,  Jelena Tošović  1 ,  Donna McEachern  1 ,  Qiuxia Li  2 ,  Farzad Sarkari  2 ,  Bo Wen  2  3 ,  Duxin Sun  2  3 ,  Shaomeng Wang  1  4  5  3
Affiliations
  • 1. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5. Department of Medicinal Chemistry, College of Pharmacy,, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39132814 DOI: 10.1021/acs.jmedchem.4c00971
Abstract

The bromodomain-containing protein BRD9 has emerged as an attractive therapeutic target. In the present study, we successfully identified a number of highly potent BRD9 degraders by using two different Cereblon ligands developed in our laboratory. Further optimization led to the discovery of CW-3308 as a potent, selective, and orally bioavailable BRD9 Degrader. It displayed degradation potency (DC50) < 10 nM and efficiency (Dmax) > 90% against BRD9 in the G401 rhabdoid tumor and HS-SY-II synovial sarcoma cell lines and had a high degradation selectivity over BRD7 and BRD4 proteins. CW-3308 achieved 91% of oral bioavailability in mice. A single oral dose efficiently reduced the BRD9 protein by >90% in the synovial sarcoma HS-SY-II xenograft tumor tissue. Oral administration effectively inhibited HS-SY-II xenograft tumor growth in mice. CW-3308 is a promising lead compound for further optimization and extensive evaluation for the treatment of synovial sarcoma, rhabdoid tumor, and Other BRD9-dependent human diseases.

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