Design, synthesis and structure-activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a clinical conundrum with distinct clinical and pathologic features, which is characterized by high aggression, poor prognosis, and lack of targeted therapies. In this study, based on the structural features of type II kinase inhibitors, we designed and synthesized a focused library of 41 pyrimidine derivatives possessing potent anti-proliferation activity, Y29 showed the most potent activity against MDA-MB-231 cells. Subsequently, we carried out target prediction, homology modeling, molecular docking, dynamics simulation and determination of enzymatic activity. The results suggested that PDGFR-β was its potential target. In vitro experiments revealed that Y29 attenuated metastasis by PDGFR-β inhibition-induced autophagy and could enhance autophagy-related cell death through AKT-MAPK feedback loop in MDA-MB-231 cells.

Keywords: Autophagy; Cell death; Metastasis; Triple-negative breast cancer.