2. Academic Validation
  3. Discovery of novel 2,4-disubstituted pyrimidines as Aurora kinase inhibitors

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.
Yu Xu 1,  Shu-Yi Hao 1,  Xiu-Juan Zhang 1,  Wen-Bo Li 1,  Xue-Peng Qiao 1,  Zi-Xiao Wang 1,  Shi-Wu Chen 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
  • 2 School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
PMID: 31862411 DOI: 10.1016/j.bmcl.2019.126885
Abstract

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.

Keywords

Anticancer; Apoptosis; Aurora kinase; Pyrimidine.

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