BETd-246

BETd-246 is a BRD2/3/4 PROTAC degrader targeting the BET family. BETd-246 induces ubiquitination and proteasomal degradation of BRD2, BRD3 and BRD4 by recruiting the CUL4-RBX1-DDB1-CRBN E3 ubiquitin ligase complex; it also inhibits TRAT1 expression and depletes BET proteins. BETd-246 suppresses cancer cell proliferation and invasion, disrupts the cell cycle and induces apoptosis. BETd-246 is applicable to research related to triple-negative breast cancer and T-cell acute lymphoblastic leukemia^[1][2]. IC50 & Target:BET BRD^[1]. In Vitro:BETd-246 (10-100 nM; 1-3 h) potently and selectively depletes BRD2, BRD3 and BRD4 in the MDA-MB-468 cell line via a proteasome-dependent mechanism mediated by the CRL4^CRBN E3 ligase, with nearly complete depletion achieved within 1-3 h^[1].
BETd-246 (3-8 h) induces a unique transcriptional response in human MDA-MB-157, MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines, and downregulates gene expression primarily in a BET degradation-dependent manner, including key proliferation and survival genes such as BRD2 and MCL1^[1].
BETd-246 (24 h) inhibits cell viability in a concentration-dependent manner, with nanomolar IC₅₀ values: MOLT4 (304.02 nM), 6T-CEM (407.2 nM), Jurkat (118.5 nM), J.gamma1 (580.2 nM), SUPT1 (320.2 nM), CCRF-CEM (307.72 nM), PF382 (441.72 nM), and CD3+ T cells (1430 nM)^[2].
BETd-246 (500-2000 nM; 24 h) induces irregular cell morphology and formation of cellular debris in J.gamma1 and 6T-CEM T-ALL cells^[2].
BETd-246 (500 nM) significantly reduces the colony-forming ability of J.gamma1 and 6T-CEM T-ALL cells^[2].
BETd-246 (5-10 nM) significantly downregulates the expression of TRAT1 mRNA in J.gamma1 T-ALL cells^[2].
BETd-246 (100 nM; 5-48 h) induces robust, CRBN-dependent apoptosis in the MDA-MB-468 cell line by activating multiple apoptotic pathways, and cleavage of key apoptotic markers is detectable within 5 h of treatment^[1].
BETd-246 (10 nM) downregulates the expression of MCL1 in human triple-negative breast cancer (TNBC) cell lines, and this downregulation plays a critical role in the potent apoptosis induction and growth inhibition mediated by BETd-246^[1].
Treatment with BETd-246 (500-2000 nM; 24 h) induces concentration-dependent apoptosis in J.gamma1 and 6T-CEM T-ALL cells, with significantly higher apoptosis rates at higher concentrations^[2]. In Vivo:BETd-246 (5-10 mg/kg; i.v.; 3 times per week; 3 weeks) inhibits growth and induces partial regression of WHIM24 breast cancer PDX tumors in SCID mice, with 10 mg/kg reducing tumor BET proteins by >80% and MCL1 levels, while exhibiting no significant toxicity^[1].
BETd-246 (5 mg/kg; i.v.; 3 times per week; 2 weeks) inhibits MDA-MB-453 breast cancer xenograft growth in SCID mice with 85% TGI, with no significant toxicity^[1].
BETd-246 (10 mg/kg; i.v.; 3 times per week; 2-3 weeks) exhibits very limited antitumor activity against MDA-MB-231 breast cancer xenografts in SCID mice, with no significant toxicity^[1].
BETd-246 (10 mg/kg; i.v.; 3 times per week; 2-3 weeks) shows no antitumor activity against MDA-MB-468 breast cancer xenografts in SCID mice, with no significant toxicity^[1].
BETd-246 (0.5 mg/kg; i.p.; daily; 9 days) significantly reduces T-ALL cell proliferation, invasion, and BRD4 expression in NSG mice, and prolongs mouse survival with good tolerability^[2].