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. Epub 2014 May 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / administration & dosage
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • MCF-7 Cells
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Thiophenes / administration & dosage
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • (5-chloro-N-(1,1-dioxo-1H-1lamda(6)-benzo(b)thiophen-6-yl)-2-hydroxybenzamide
  • Antineoplastic Agents
  • Benzamides
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Small Molecule Libraries
  • Thiophenes