BETd-246 is an inhibitor of second-generation and PROTAC-based BET bromodomain (BRD), show antitumor activity.

BETd-246 treatment (0-100 nM, 1-3 h) leads to a dose-dependent reduction of BRD2, BRD3, and BRD4 in TNBC cell lines, with optimal effects observed at 30-100 nM for 1 hour or 10-30 nM for 3 hours. BETd-246 (100 nM, 24/48 hours) significantly inhibits growth and induces apoptosis in MDA-MB-468 cell lines. Additionally, BETd-246 (100 nM, 24 hours) causes marked cell cycle arrest and apoptosis in TNBC cell lines[1]. It induces rapid, time-dependent downregulation of MCL1 protein in all evaluated TNBC cell lines and exhibits stronger apoptosis induction than BETi-211.

BETd-246 (5 mg/kg, IV, 3 times per week for 3 weeks) effectively inhibits WHIM24 tumor growth, similar to the antitumor activity of BETi-211 at a higher dose with more frequent administration. BETd-246 exhibits limited drug exposure in xenograft tumor tissue in MDA-M-231 and MDA-MB-468 models[1]. A dose of 10 mg/kg induces partial tumor regression during treatment without apparent toxicity.