Benzo[c][1,2,5]thiadiazole derivatives: A new class of potent Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors

Wen-Long Wang; Xiao-Yu Chen; Ya Gao; Li-Xin Gao; Li Sheng; Jingyu Zhu; Lei Xu; Zhen-Zhong Ding; Chao Zhang; Jing-Ya Li; Jia Li; Yu-Bo Zhou

doi:10.1016/j.bmcl.2017.10.059

Benzo[c][1,2,5]thiadiazole derivatives: A new class of potent Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5154-5157. doi: 10.1016/j.bmcl.2017.10.059. Epub 2017 Oct 26.

Authors

Wen-Long Wang¹, Xiao-Yu Chen², Ya Gao², Li-Xin Gao³, Li Sheng³, Jingyu Zhu², Lei Xu⁴, Zhen-Zhong Ding⁵, Chao Zhang⁵, Jing-Ya Li³, Jia Li³, Yu-Bo Zhou⁶

Affiliations

¹ School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
² School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
³ State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China.
⁵ YangZhou RiXing Bio-Tech Co., Ltd, Yangzhou 225601, China.
⁶ State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].

PMID: 29100798
DOI: 10.1016/j.bmcl.2017.10.059

Abstract

The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC₅₀ of 2.11 ± 0.99 μM, exhibited 2.02-fold and 25-fold selectivity for SHP2 over SHP1 and PTP1B respectively and had no visible activity against TCPTP. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors with optimal potency and improved pharmacological properties.

Keywords: Benzo[c][1,2,5]thiadiazole derivatives; Inhibitors; PTP1B; SHP2; Structure-activity relationships (SAR).

Publication types

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

MeSH terms

Binding Sites
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Protein Domains
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Structure-Activity Relationship
Thiadiazoles / chemistry*
Thiadiazoles / metabolism

Substances

Enzyme Inhibitors
Thiadiazoles
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatase, Non-Receptor Type 11