Design, synthesis and anti-ovarian cancer activities of thieno[2,3-d]pyrimidine based chimeric BRD4 inhibitor/nitric oxide-donator

Bromodomain protein 4 (BRD4) is an attractive epigenetic target that regulating diverse cellular processes, and the discovery of dual-target inhibitors including BRD4 is an effective approach in cancer treatment to increase potency and reduce drug resistance. Based on the multifunctional drug development strategy, a series of new derivatives of nitrooxy (ONO2) or furoxan (1,2,5-oxadiazole 2-oxide) with BRD4 inhibitor capable of inhibiting BRD4 and simultaneously releasing NO were designed and synthesized. When NO concentrations were measured with Griess reagent under physiological conditions, all compounds released NO at micromolar levels, reaching effective antitumor concentrations. Biological studies showed that the most potent BRD4/NO hybrid 11a exhibited good BRD4 inhibitory activity and selectivity. Further mechanistic studies revealed that 11a significantly decreased the expression of BRD4 and c-Myc, as well as induced cellular apoptosis and autophagic cell death both in vitro and in vivo. In summary, we optimized the chimeric BRD4-inhibitor/NO-donor based on our previous studies, and it should be a lead compound for targeted therapy of OC (ovarian cancer) in the future. This interesting strategy could expand the usage of BRDi in human malignancies and endogenous gastro-transmitters.