Small Molecule BET Bromodomain Inhibitors for the Treatment of Cancer and Inflammatory Diseases

This technology includes a new chemical series of substituted bicyclic heteroaryl small molecules as potent bromodomain-containing protein BRD4 inhibitors used for the treatment of cancer and inflammatory diseases. The optimization led to compounds with good potency in enzymatic assay ( 100 nM) and in MV4-11 cell-based assay ( 1000 nM) as well as excellent early ADME properties. We also identified N-methyl 2 pyridone and N-methyl pyrrolopyridone are great replacements of di-methylisoxazole. This chemical series also exhibited good ADME profiles, including PK. From recent data indicated that the selected analogs also potently inhibited bromodomain of CBP/p300. The selected analogs demonstrated in vivo efficacy in cancer xenograft models and in inflammatory disease models.