DESIGN AND SYNTHESIS OF DUAL HER-2 AND PI3 KINASE INHIBITORS FOR THE TREATMENT OF BREAST CANCER: A MULTIDIMENSIONAL APPROACH

Abstract

Breast cancer is the most commonly found cancer in women and the incidence is high in developing countries. Very few HER-2 tyrosine kinase inhibitors available in the market, but chronic use of some of these inhibitors may result in resistant to the treatment. The dual inhibition of HER-2 and PI3K tyrosine kinases can effectively treat breast cancers. In view of this, the present investigation is directed to the design of dual HER-2 and PI3K inhibitors employing a multidimensional drug design approach. In this approach, molecular docking studies of some existing HER-2 and PI3K inhibitors were carried out and physicochemical properties were also considered to identify common structural features for dual inhibition. From these results, new dual HER-2 and PI3K inhibitors were designed. Among some of the designed molecules new thienopyrimidines were synthesized and tested for anti-proliferative activity on breast cancer cell lines. Finally, six heterocyclic core moieties and important substituents were identified for HER-2 and PI3K selectivity. Among them thienopyrimidine was selected for the synthesis. Some of the synthesized compounds were found to show appreciable anti-proliferative activity in the in vitro cytotoxicity studies.