上海科技大学知识管理系统

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 EC 50 of 5.48 & PLUSMN; 0.28 & mu;mol/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.& COPY; 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.