Discovery of thieno[2,3-d]pyrimidine based hydroxamic acid derivatives as bromodomain-containing protein 4/histone deacetylases dual inhibitors induce autophagic cell death in colorectal carcinoma cells.

BRD4 and HDAC are both attractive epigenetics targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4/HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest the BRD4/HDAC dual inhibition might be an attractive therapeutic strategy for colorectal carcinoma.