Title:Design, Synthesis and Evaluation of Quinoline-based Small Molecule Inhibitor of STAT3
VOLUME: 10 ISSUE: 5
Author(s):Zhi-Bing Shi, Lei Zhang, Zheng-Yang Bin, Xiang-Rong Cao, Zhu-Nan Gong and Jian-Xin Li
Affiliation:State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China.
Keywords:2-Phenyl quinoline-4-carboxylic acid, Breast cancer cell lines, Quinoline, SH2 domian, Small molecule inhibitor,
STAT3
Abstract:As STAT3 has been validated as an anticancer target, its inhibitors have been shown to possess therapeutic
promise for the treatment of human cancers. To identify novel and selective STAT3 inhibitors, a virtual screening based
on the STAT3 SH2 domain was performed and a small molecule, 2-phenylquinoline-4-carboxylic acid (5a), with an inhibition
constant Ki value of 17.53 μM to STAT3 was discovered. On this basis, the derivatives of 5a including esters, amides
and dimers were synthesized. The bioactivity and inhibitory selectivity of the derivatives were assayed using human
breast cancer cell lines, MDA-MB-468 and MCF-7. Among the derivatives, 5c and 9b showed the most potent inhibitory
activity with a good selectivity, and also inhibited STAT3 protein level of MDA-MB-468 cells. The results demonstrated
a successful application of virtual screening for lead discovery. Compound 9b might be an effective STAT3 inhibitor lead
for the further development of antitumor agents.
