title: Discovery of an Orally Selective Inhibitor of Signal Transducer and Activator of Transcription 3 Using Advanced Multiple Ligand Simultaneous Docking.
abstract: Targeting signal transducer and activator of transcription 3 (STAT3) is a potential anticancer strategy. However, STAT3 inhibitors with good selectivity and bioavailability are rare. The aim of this study was to discover selective direct STAT3 inhibitors with good druglikeness. By the advanced multiple ligand simultaneous docking (AMLSD) method, compound 9 was designed as an orally bioavailable STAT3 inhibitor that presented superior druggability and selectivity compared with other representative STAT3 inhibitors. 9 directly and selectively inhibited the pY705 site of STAT3 with an affinity (Ki) of 440 nM. The IC50of 9 for MDA-MB-231 breast cancer cells was 184-fold lower than its IC50for MCF-10A normal breast epithelial cells. 9 in vivo induced significant antitumor responses (better than gefitinib), and its therapeutic index should be over 100, indicating good safety of 9.
authors.forename: Wenying
authors.initials: W
authors.lastname: Yu
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Wenda
authors.initials: W
authors.lastname: Zhang
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Xia
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Jia-Yuh
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Water Supply and Drainage, Nanchang Hangkong University , 696 Fenghe Avenue South, Nanchang 330046, China.
authors.forename: Keqin
authors.initials: K
authors.lastname: Yu
authors.forename: Mu
authors.initials: M
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Jianguang
authors.initials: J
authors.lastname: Luo
authors.forename: Yijun
authors.identifier: 0000-0002-4920-152X
authors.initials: Y
authors.lastname: Chen
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
authors.forename: Lingyi
authors.identifier: 0000-0001-9712-2618
authors.initials: L
authors.lastname: Kong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor