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.

Philias Daka ¹, Aiguo Liu ², Chamini Karunaratne ¹, Erika Csatary ¹, Cameron Williams ¹, Hui Xiao ³, Jiayuh Lin ³, Zhenghu Xu ⁴, Richard C Page ⁵, Hong Wang ⁶

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.

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