PROTAC BRD2/BRD4 degrader-1 (compound 15) is a potent, selective degrader of BET proteins BRD4 and BRD2, achieving rapid, reversible, and unexpectedly selective elimination compared to BRD3. It effectively suppresses solid tumors with minimal cytotoxic effects and comprises a BET inhibitor, a connecting linker, and thalidomide as the ligand for cereblon (CRBN)/cullin 4A[1].

PROTAC BRD2/BRD4 degrader-1 (100 nM; ≥8 hours) demonstrates significant anti-proliferative activity with an IC50 value of 12.25 nM and effectively reduces BRD4 protein levels in MV4-11 cells at treatment times of ≥8 hours. Additionally, it induces apoptosis in MV4-11 cells at concentrations of (1 nM, 3 nM, 0.1 μM, 0.3 μM; 24-48 hours). This compound shows excellent anti-proliferative activity across six leukemia cell lines from NCI, with GI50 values below 50 nM in three of these lines, aligning with its activity in MV4-11 cells. It also exhibits considerable anti-proliferative effects in prostate cancer (22RV1 IC50: 0.081 μM), colon cancer (colo-205 IC50: 0.1557 μM), and thyroid cancer (TT IC50: 0.037451 μM) cells[1].