High throughput in silico screening and in vitro testing of polypharmacological bromodomain 4 and cancer associated kinase inhibitors

Abstract

Polypharmacology has recently become an intense subject of research, specifically in the development and design of anti-cancer compounds. Drugs that have more than one target, potentially have higher efficacy in the treatment of triple negative breast cancer and prevent the development of drug resistance. Bromodomain containing protein 4 (BRD4) is a known dysregulated enzyme in triple negative breast cancer, together with other kinases such as aurora kinase A and B (AURKA and AURKB), cyclin dependant kinases 4 and 6 (CDK4/6), polo-like kinase (PLK1) and epidermal growth factor receptor (EGFR). The research set out to identify a poly-inhibitors of BRD4 and cancer associated kinases, using virtual high throughput screening. The 10 promising compounds have either imidazo[1,2-b]pyridazine or 1H-imidazo[4,5-c]pyridine backbones in their chemical structure. The 10 poly-inhibitors underwent in vitro screening from which one compound was identified as being active. Further in vitro assays were performed to elucidate its effect on TNBCs in vitro.