Discovery of TK-642 as a highly potent,selective,orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor  

作　　者：Kai Tang Shu Wang Siqi Feng Xinyu Yang Yueyang Guo Xiangli Ren Linyue Bai Bin Yu Hong-Min Liu Yihui Song 

机构地区：[1]School of Pharmaceutical Sciences&Key Laboratory of Advanced Drug Preparation Technologies,Ministry of Education,Zhengzhou University,Zhengzhou 450001,China [2]College of Chemistry,Pingyuan Laboratory,State Key Laboratory of Antiviral Drugs,Zhengzhou University,Zhengzhou 450001,China [3]Tianjian Laboratory of Advanced Biomedical Sciences,Institute of Advanced Biomedical Sciences,Zhengzhou University,Zhengzhou 450000,China [4]State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing 210023,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3624-3642,共19页药学学报（英文版）

基　　金：the financial support from the Natural Science Foundation of China(Nos.U21A20416,32371317,22277110,and 82104279);Natural Science Foundation of Henan Province(No.222300420069,China);“Chunhui Plan”Cooperative Scientific Research Project of the Ministry of Education(No.HZKY20220280,China);State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University(KF-202303,China)。

摘　　要：Src homology-2-containing protein tyrosine phosphatase 2(SHP2)is a promising therapeutic target for cancer therapy.In this work,we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors,leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent,selective,orally bioavailable allosteric SHP2 inhibitor(SHP2WT IC_(50)=2.7 nmol/L)with favorable pharmacokinetic profiles(F=42.5%;t_(1/2)=2.47 h).Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the“tunnel”allosteric site of SHP2.TK-642 could effectively suppress cell proliferation(KYSE-520 cells IC_(50)=5.73μmol/L)and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways.Additionally,oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model,with a T/C value of 83.69%.Collectively,TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

关 键 词：Protein tyrosine phosphatase Pyrazolopyrazine SHP2 inhibitor Esophageal cancer 

分 类 号：R91[医药卫生—药学]