In previous blogs, we have introduced a lot of PROTAC based degraders, including TD-428, HJB97, A1874, etc. Coincidentally most of them are all PROTAC-based BET degraders. Today, I’d like to introduce another PROTAC-based BET bromodomain (BRD) inhibitor, BETd-246.

Bromodomain and Extra Terminal (BET) proteins are epigenetic “readers” and play a major role in epigenetic regulation of gene transcription. BET proteins have emerged as new therapeutic targets for human cancer and other diseases. Early clinical trials have provided evidence that inhibition of BET proteins is effective against some human cancers, including NUT midline carcinoma, multiple myeloma and acute myeloid leukemia. Recent preclinical studies further suggested that BET proteins are exciting targets for breast cancer.

BETd-246 is a second-generation and PROTAC-based BET bromodomain (BRD) inhibitor, exhibiting superior selectivity, potency and antitumor activity.

In vitro, On the one hand, BETd-246 treatment (0-100 nM, 1-3 h) causes a dose-dependent depletion of BRD2, BRD3, and BRD4 in representative TNBC cell lines with 30-100 nM for 1 h or with 10-30 nM for 3 h incubation. On the other hand, BETd-246 (100 nM, 24/48 hours) displays strong growth inhibition and apoptosis induction activity in MDA-MB-468 cell lines. What’s more, BETd-246 induces a rapid and time-dependent downregulation of MCL1 protein in all the TNBC cell lines evaluated. BETd-246 induces much stronger apoptosis than BETi-211. Not only that, but BETd-246 (100 nM, 24 hours) also induces pronounced cell cycle arrest and apoptosis in TNBC cell lines.

In addition, in vivo, BETd-246 (5 mg/kg, IV, 3 times per week for 3 weeks) treatment effectively inhibits WHIM24 tumor growth, similar to the antitumor activity of BETi-211 with higher dosage and more frequent administration. The treatment of 10 mg/kg induces partial tumor regression during treatment without apparent toxicity. BETd-246 has very limited drug exposure in the xenograft tumor tissue in MDA-M-231and MDA-MB-468 models.

In total, BETd-246 stands of a potential PTOTAC BET inhibitor for breast cancer (TNBC) treatment.


Bai L, et al. Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer. Cancer Res. 2017 May 1;77(9):2476-2487.