2. Academic Validation
  3. Discovery of an Orally Selective Inhibitor of Signal Transducer and Activator of Transcription 3 Using Advanced Multiple Ligand Simultaneous Docking

Discovery of an Orally Selective Inhibitor of Signal Transducer and Activator of Transcription 3 Using Advanced Multiple Ligand Simultaneous Docking

  • J Med Chem. 2017 Apr 13;60(7):2718-2731. doi: 10.1021/acs.jmedchem.6b01489.
Wenying Yu,  Chenglong Li 1,  Wenda Zhang,  Yuanzheng Xia,  Shanshan Li,  Jia-Yuh Lin 2,  Keqin Yu 3,  Mu Liu,  Lei Yang,  Jianguang Luo,  Yijun Chen,  Hongbin Sun,  Lingyi Kong
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
  • 2 Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland , Baltimore, Maryland 21201, United States.
  • 3 Water Supply and Drainage, Nanchang Hangkong University , 696 Fenghe Avenue South, Nanchang 330046, China.
PMID: 28245116 DOI: 10.1021/acs.jmedchem.6b01489
Abstract

Targeting signal transducer and activator of transcription 3 (STAT3) is a potential Anticancer strategy. However, STAT3 inhibitors with good selectivity and bioavailability are rare. The aim of this study was to discover selective direct STAT3 inhibitors with good druglikeness. By the advanced multiple ligand simultaneous docking (AMLSD) method, compound 9 was designed as an orally bioavailable STAT3 Inhibitor that presented superior druggability and selectivity compared with Other representative STAT3 inhibitors. 9 directly and selectively inhibited the pY705 site of STAT3 with an affinity (Ki) of 440 nM. The IC50 of 9 for MDA-MB-231 breast Cancer cells was 184-fold lower than its IC50 for MCF-10A normal breast epithelial cells. 9 in vivo induced significant antitumor responses (better than gefitinib), and its therapeutic index should be over 100, indicating good safety of 9.

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