title: Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3).
abstract: In a continuing effort to develop orally bioavailable small-molecule STAT3 inhibitors as potential therapeutic agents for human cancer, a series of novel diversified analogues based on our identified lead compound HJC0149 (1) (5-chloro-N-(1,1-dioxo-1H-1λ(6)-benzo[b]thiophen-6-yl)-2-hydroxybenzamide, Eur. J. Med. Chem. 2013, 62, 498-507) have been rationally designed, synthesized, and pharmacologically evaluated. Molecular docking studies and biological characterization supported our earlier findings that the O-alkylamino-tethered side chain on the hydroxyl group is an effective and essential structural determinant for improving biological activities and druglike properties of these molecules. Compounds with such modifications exhibited potent antiproliferative effects against breast and pancreatic cancer cell lines with IC50 values from low micromolar to nanomolar range. Among them, the newly discovered STAT3 inhibitor 12 (HJC0416) displayed an intriguing anticancer profile both in vitro and in vivo (i.p. & p.o.). More importantly, HJC0416 is an orally bioavailable anticancer agent as a promising candidate for further development.
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States; College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian 350002, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Zhengduo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Ailian
authors.initials: A
authors.lastname: Xiong
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wild
authors.affiliation: Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Na
authors.initials: N
authors.lastname: Ye
authors.affiliation: Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Guoshuai
authors.initials: G
authors.lastname: Cai
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Rudolfo M
authors.initials: RM
authors.lastname: Flores
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States. Electronic address: qshen@mdanderson.org.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000595831:(5-chloro-N-(1,1-dioxo-1H-1lamda(6)-benzo(b)thiophen-6-yl)-2-hydroxybenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D054852:Small Molecule Libraries; D013876:Thiophenes
keywords: Anticancer agents; Breast cancer; Oral bioavailability; Pancreatic cancer; STAT3 inhibitors