2. Academic Validation
  3. Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

  • Eur J Med Chem. 2014 Jul 23;82:195-203. doi: 10.1016/j.ejmech.2014.05.049.
Haijun Chen 1,  Zhengduo Yang 2,  Chunyong Ding 3,  Ailian Xiong 2,  Christopher Wild 3,  Lili Wang 2,  Na Ye 3,  Guoshuai Cai 2,  Rudolfo M Flores 3,  Ye Ding 3,  Qiang Shen 4,  Jia Zhou 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
  • 4 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.
  • 5 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.
PMID: 24904966 DOI: 10.1016/j.ejmech.2014.05.049
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.

Keywords

Anticancer agents; Breast cancer; Oral bioavailability; Pancreatic cancer; STAT3 inhibitors.

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