title: Discovery, synthesis, and evaluation of small-molecule signal transducer and activator of transcription 3 inhibitors.
abstract: 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 K(i) 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.
authors.affiliation: State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China.
authors.forename: Zhi-Bing
authors.initials: ZB
authors.lastname: Shi
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Huang
authors.forename: Yun
authors.initials: Y
authors.lastname: Du
authors.forename: Xiang-Rong
authors.initials: XR
authors.lastname: Cao
authors.forename: Zhu-Nan
authors.initials: ZN
authors.lastname: Gong
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human