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

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.