Synthesis and identification of a novel skeleton of N-(pyridin-3-yl) proline as a selective CDK4/6 inhibitor with anti-breast cancer activities

[Display omitted] •Fragment based drug discovery.•A series of novel CDK4/6 selective inhibitors with anti-breast cancer activities.•Small molecule deconstruction and structure activity relationship based on descriptor method.•Discovery of a new potential binding mode of small molecule& CDK4/6 mediated by Ile12. CDK4/6 were attractive chemotherapeutic targets for the treatment of malignant tumors, CDK4/6 selective inhibitors have made outstanding contributions in the treatment of breast cancer. However, these inhibitors share a single skeleton of N-(pyridin-2-yl) pyrimidin-2-amine which cannot overcome the side effects in clinical application. In our previous study, an N'- acetylpyrrolidine-1-carbohydrazide was hit as the initial fragment by analyzing the active site characteristics of CDK6. Two series of N-(pyridin-3-yl) proline were obtained by fragment growth method. The QSAR study was carried out according to the in vitro activities data against CDK4/6, and two compounds 7c and 7p with potent inhibitory activities were found to interact with CDK4 in different binding conformation. They showed potential inhibition of cell proliferation against the breast cancer cell, and 7c exhibited promised anti-breast cancer effect in vivo.