Targeting aromatase to restrain oestrogen production and developing efficacious interventions against ER-positive cancer

Being the most frequently diagnosed disease, breast cancer is mainly classified as ER+ cancers due to the detection of estrogen receptor (ER) expression. Irrespetive of the successes achieved in the treatment of ER+ cancers by the use of selective estrogen receptor modulator (SERM) drugs like tamoxifen, resistance to the drug is a major clinical obstacle. Working on alternative treatment approaches, here, on the basis of mode of action of aromatase for the conversion of androstenedione to oestrogen, a series of compounds was developed. Results of all the experiments performed with these compounds led to the identification of three highly potent compounds 5d, 5e and 7d with their IC50 61.0, 83.0 and 54.0 nM for aromatase. Indicating their effectiveness in the treatment of ER+ cancers, appreciable tumor growth inhibitory activities of these compounds were observed against breast cancer cell lines. Further, the physico-chemical experiments including plasma protein binding, HSA binding, kinetic studies, solubility, ADME properties and molecular modelling studies supported the drug like features of the compounds.