SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis
Meijing Wang,
Tinghan Li,
Zijun Ouyang,
Kai Tang,
Yuyu Zhu,
Chenglin Song,
Haiyan Sun,
Bin Yu,
Xiaoyun Ji,
Yang Sun
Affiliations
Meijing Wang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
Tinghan Li
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
Zijun Ouyang
Institute of Marine Biomedicine, School of Food and Drug, Shenzhen Polytechnic, 7098 Liuxian Avenue, Shenzhen, Guangdong 518055, China
Kai Tang
School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
Yuyu Zhu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
Chenglin Song
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
Haiyan Sun
Institute of Marine Biomedicine, School of Food and Drug, Shenzhen Polytechnic, 7098 Liuxian Avenue, Shenzhen, Guangdong 518055, China
Bin Yu
School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Corresponding author
Xiaoyun Ji
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China; Corresponding author
Yang Sun
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China; Corresponding author
Summary: SHP2 is the first oncogenic tyrosine phosphatase encoded by PTPN11, which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 Å shift of the dichlorophenyl ring and an approximate 20° deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis.
