vx680 and 2-4-diaminopyrimidine

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 μM. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.

Topics: Aurora Kinase A; Aurora Kinase B; Cell Cycle; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; HeLa Cells; Humans; Immunoblotting; Molecular Docking Simulation; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyrimidines