Discovery, Synthesis, and Evaluation of Small-Molecule Signal Transducer and Activator of Transcription 3 Inhibitors

概要

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The signal transducer and activator of transcription 3 (STAT3) oncogene is a promising molecular target and its inhibitors have great potential as anticancer drugs. To identify novel and STAT3-selective inhibitors, a virtual screening based on Specs and Maybridge databases was conducted and a 6,6′-bibenzoxazole type small molecule, compound 3a with a inhibition constant Ki value of 494.32 nM to STAT3 was explored. Further, a novel series of derivatives originally derived from 3a was synthesized and evaluated through cell-based assays using human breast cancer cell lines, MDA-MB-468 and MCF-7 with or without constitutive expression of STAT3, respectively. In the series, 3a, 3c, 3d and 4e showed a better inhibitory activity with a good selectivity. Among them, 3a and 3c significantly inhibited STAT3 protein level and also displayed binding affinity for STAT3 that detected with flow injection analysis-quartz crystal microbalance (FIA-QCM) analysis system. The results provided a new lead for future design and development of potent STAT3 inhibitors.