title: Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy.
abstract: Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy.
authors: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors: Haijun
authors: H
authors: Chen
authors: Zhengduo
authors: Z
authors: Yang
authors: Chunyong
authors: C
authors: Ding
authors: Lili
authors: L
authors: Chu
authors: Yusong
authors: Y
authors: Zhang
authors: Kristin
authors: K
authors: Terry
authors: Huiling
authors: H
authors: Liu
authors: Qiang
authors: Q
authors: Shen
authors: Jia
authors: J
authors: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C583783:2-phenylquinoline-4-carboxylic acid (1,1-dioxo-1H-1lambda6-benzo(b)thiophen-6-yl)amide; D000970:Antineoplastic Agents; D011804:Quinolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013876:Thiophenes