Long-sought inhibitor found for cancer-related enzyme

Abstract

A novel strategy could break a two-decade impasse in efforts to find clinically developable drug inhibitors of SHP2, a phosphatase enzyme that plays an important role in many cancers. Activation of SHP2 by proteins overexpressed in cancer, such as endothelial growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), promotes tumor growth. But SHP2 helps stimulate cancer growth only when it adopts an open conformation, in which its three domains fan out and its active site becomes exposed. In 20-odd years of efforts to inhibit SHP2, researchers have tried to target the active site in the open conformation. The problem is that the negatively charged compounds they’ve used to inhibit SHP2’s polar active site do not make good drugs because they are not able to cross cell membranes easily or enter the bloodstream effectively when administered orally. So those SHP2 inhibitors haven’t worked well therapeutically, and none