Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines.

[Display omitted] • A novel series of p300 bromodomain inhibitors were discovered and more tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. • Compound B4 showed potent p300 bromodomain inhibitory activity and improved proliferation inhibition on sensitive tumor cells than CCS1477. • Compound B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. • Compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk. p300/CBP bromodomain plays an important role in transcriptional regulation, and its overexpression is closely related to various diseases such as cancers. Two inhibitors of this target are currently in clinical trials but only CCS1477 (A1) have been published with the chemical structure. Herein, we modified the structure of CCS1477 based on the principle of bioisosterism and reasonable scaffold hopping, and discovered a series of new p300 bromodomain inhibitors with improved potency. More tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. Among our new inhibitors, (R)-5-methylpyrrolidin-2-one derivitive B4 was the most potent one which showed comparable inhibitory activity against p300 (IC 50 = 0.060 μM) as lead A1 (IC 50 = 0.064 μM) at molecular level, and performed more potent proliferation inhibitory activities on various tumor cells than A1. Further we found that compound B4 had the high cell permeability and overcame the defect of the high efflux rate of A1 , which could also explain the possible reason why B4 showed more potent inhibitory activities on sensitive tumor cells than lead A1. Western blotting analysis proved the target effects that B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. Liver microsomal metabolic stability assay and hERG channel inhibition evaluation illustrate compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk, which further demonstrate the good drug-likeness of B4. Therefore, compound B4 is a promising compound for further optimization and development. [ABSTRACT FROM AUTHOR]