Discovery of\nCW-3308 as a Potent, Selective, and Orally\nEfficacious PROTAC Degrader of BRD9

The bromodomain-containing protein BRD9 has emerged as\nan attractive\ntherapeutic target. In the present study, we successfully identified\na number of highly potent BRD9 degraders by using two different cereblon\nligands developed in our laboratory. Further optimization led to the\ndiscovery of CW-3308 as a potent, selective, and orally bioavailable\nBRD9 degrader. It displayed degradation potency (DC<sub>50</sub>)\n< 10 nM and efficiency (<i>D</i><sub>max</sub>) >\n90%\nagainst BRD9 in the G401 rhabdoid tumor and HS-SY-II synovial sarcoma\ncell lines and had a high degradation selectivity over BRD7 and BRD4\nproteins. CW-3308 achieved 91% of oral bioavailability in mice. A\nsingle oral dose efficiently reduced the BRD9 protein by >90% in\nthe\nsynovial sarcoma HS-SY-II xenograft tumor tissue. Oral administration\neffectively inhibited HS-SY-II xenograft tumor growth in mice. CW-3308\nis a promising lead compound for further optimization and extensive\nevaluation for the treatment of synovial sarcoma, rhabdoid tumor,\nand other BRD9-dependent human diseases.