Novel thieno[2,3-b]quinoline-procaine hybrid molecules:A new class of allosteric SHP-1 activators evolved from PTP1B inhibitors  

作　　者：Lei Xu Xuyang Mu Minmin Liu Zhijia Wang Chao Shen Qianwen Mu Bo Feng Yechun Xu Tingjun Hou Lixin Gao Haini Jiang Jia Li Yubo Zhou Wenlong Wang 

机构地区：[1]School of Life Sciences and Health Engineering,Jiangnan University,Wuxi 214122,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan 528400,China [4]School of Chemical and Material Engineering,Jiangnan University,Wuxi 214122,China [5]Innovation Institute for Artificial Intelligence in Medicine,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [6]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China

出　　处：《Chinese Chemical Letters》2023年第8期213-218,共6页中国化学快报（英文版）

基　　金：supported by National Natural Science Foundation of China(Nos.81773779,21772068 and 22277043);National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(No.2018ZX09711002-007-1);Natural Science Foundation of Jiangsu Province(No.BK20190608);Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX22_2330).

摘　　要：Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction.However,targeted protein activation is chemically challenging.Developing activators against Src homology region 2 domain-containing phosphatase-1(SHP-1)to block STAT3 pathway represents a promising strategy for DLBCL therapy.Here we reported a new class of thieno[2,3-b]quinolineprocaine hybrid molecules as SHP-1 allosteric activators.The representative hybrid compound 3b displayed SHP-1 activating effect with EC50 of 5.48±0.28μmol/L.Further investigations confirmed that 3b allosterically interacted with SHP-1,switched it from close to open conformation,blocked SHP-1/p-STAT3 pathway,induced apoptosis and inhibited ABC-DLBCL cell proliferation in vitro,and delayed tumor growth in the xenograft model of SU-DHL-2.Overall,this work offered a novel paradigm to develop SHP-1 allosteric activators through chemical space evolution of PTPs inhibitors,and firstly validated the therapeutic strategy that directly activating SHP-1 alone could be a potential therapy against ABC-DLBCL via blocking STAT3 pathway.

关 键 词：Activator PTPs Inhibitor Thieno[2 3-b]quinoline derivatives Diffuse large B-cell lymphoma 

分 类 号：TQ460.1[化学工程—制药化工]