Discovery of novel 2,4-disubstituted pyrimidines as Aurora kinase inhibitors
- Bioorg Med Chem Lett. 2020 Feb 1;30(3):126885. doi: 10.1016/j.bmcl.2019.126885.
- 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
- 2. School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
In order to explore novel Aurora Kinase inhibitors, a series of novel 2,4-disubstituted pyrimidines were designed, synthesized and evaluated their in vitro anti-proliferative activities against a panel of cancerous cell lines (A549, HCT-116 and MCF-7). Among them, compound 12a showed the moderate to high anti-proliferative activities against A549 (IC50 = 12.05 ± 0.45 μM), HCT-116 (IC50 = 1.31 ± 0.41 μM) and MCF-7 (IC50 = 20.53 ± 6.13 μM) cells, as well as the Aurora A and Aurora B inhibitory activities with the IC50 values of 309 nM and 293 nM, respectively. Furthermore, compound 12a induced Apoptosis by upregulated the pro-apoptotic proteins Bax and decreased the anti-apoptotic protein Bcl-xL in HCT-116 cells. Moreover, the molecular docking study showed that compound 12a had good binding modes with Aurora A and Aurora B and the bioinformatics prediction discovered that compound 12a exhibited good drug likeness using SwissADME. Taken together, these results indicated that 12a may be a potential Anticancer compound that was worthy of further development as Aurora Kinase Inhibitor.