BETd-260, a PROTAC linked by a Cereblon ligand and a BET ligand, has an inhibitory effect on BRD4 protein in leukemic cell lines.

BRD2:30-100 pM, BRD4:<30 pM, BRD3:30-100 pM, BRD:0.0022 μM

betd - 260 (ZBC260; Compound 23) induced the degradation of BRD2, BRD3 and BRD4 proteins. BETd-260 acted on RS4; The ic50 measured for 11 leukemic cells was 51 pM. The ic50 of BETd-260 in MOLM-13 cells was 2.2 nM. BETd-260 at 3-10 nM could induce RS4; 11 and MOLM-13 cell apoptosis. Moreover, BETd-260 inhibited the transcription and translation of anti-apoptotic genes Mcl-1, Bcl-2, c-Myc and XIAP and increased the transcription and translation of pro-apoptotic gene Bad in HCC cells[1].

BETd-260, administered intravenously at a dosage of 5 mg/kg, effectively degrades the proteins BRD2, BRD3, and BRD4, maintaining this activity for over 24 hours. This process is accompanied by significant PARP and caspase-3 cleavage, along with a marked reduction in c-Myc protein levels in the RS4;11 xenograft mouse model[1]. When administered bi-weekly, three times a week for three weeks, BETd-260 induces rapid tumor regression, achieving a peak regression greater than 90% in RS4;11 xenograft tumor-bearing mice. Notably, this treatment regimen does not lead to weight loss or other toxicity symptoms in the mice.