Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy

Haijun Chen, Zhengduo Yang, Chunyong Ding, Lili Chu, Yusong Zhang, Kristin Terry, Huiling Liu, Qiang Shen, Jia Zhou

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 IC 50 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.

Original languageEnglish (US)
Pages (from-to)498-507
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume62
DOIs
StatePublished - Apr 2013

Fingerprint

Drug Design
Breast Neoplasms
Pancreatic Neoplasms
Heterografts
Caspase 3
Estrogen Receptors
Pharmaceutical Preparations
Antineoplastic Agents
Neoplasms
Cell Cycle
Down-Regulation
Cells
Phosphorylation
Pharmacology
Apoptosis
Molecules
Therapeutics
Growth
Scaffolds
Tumors

Keywords

  • Anticancer agents
  • Breast cancer
  • Drug discovery
  • Fragment-based drug design
  • STAT3

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy. / Chen, Haijun; Yang, Zhengduo; Ding, Chunyong; Chu, Lili; Zhang, Yusong; Terry, Kristin; Liu, Huiling; Shen, Qiang; Zhou, Jia.

In: European Journal of Medicinal Chemistry, Vol. 62, 04.2013, p. 498-507.

Research output: Contribution to journalArticle

Chen, Haijun ; Yang, Zhengduo ; Ding, Chunyong ; Chu, Lili ; Zhang, Yusong ; Terry, Kristin ; Liu, Huiling ; Shen, Qiang ; Zhou, Jia. / Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy. In: European Journal of Medicinal Chemistry. 2013 ; Vol. 62. pp. 498-507.
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