Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors

Philias Daka; Aiguo Liu; Chamini Karunaratne; Erika Csatary; Cameron Williams; Hui Xiao; Jiayuh Lin; Zhenghu Xu; Richard C Page; Hong Wang

doi:10.1016/j.bmc.2015.01.025

Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors

Bioorg Med Chem. 2015 Mar 15;23(6):1348-55. doi: 10.1016/j.bmc.2015.01.025. Epub 2015 Jan 22.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
² Department of Pediatrics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, PR China.
³ Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH, USA; Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA.
⁴ School of Chemistry and Chemical Engineering, Shandong University, Jinan, PR China.
⁵ Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA. Electronic address: pagerc@miamioh.edu.
⁶ Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA. Electronic address: wangh3@miamioh.edu.

PMID: 25698618
DOI: 10.1016/j.bmc.2015.01.025

Abstract

Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5μM in breast cancer cell lines and 7.6μM in pancreatic cancer cell lines were identified.

Keywords: Inhibitor; Molecular docking; SARs; SH2; STAT3; Small organic molecule.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Histidine / analogs & derivatives*
Histidine / chemical synthesis
Histidine / chemistry
Histidine / pharmacology
Humans
Molecular Structure
Phenylurea Compounds / chemical synthesis*
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology*
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Phenylurea Compounds
STAT3 Transcription Factor
STAT3 protein, human
XZH-5 compound
Histidine