Structure-Guided Design of Pyrazolopyrimidinones as Highly Potent and Selective Allosteric SHP2 Inhibitors

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays crucial roles in various biological processes and has become a promising target for cancer therapy. In this work, we presented the structure-guided design of new allosteric SHP2 inhibitors, leading to the identification of the pyrazolopyrimidinone derivatives <b>TK-684</b> and <b>TK-685</b>. Both compounds were highly potent and selective allosteric SHP2 inhibitors (<b>TK-684</b>: SHP2^WT IC₅₀ = 2.1 nM; <i>K</i>_<i>i</i> = 0.89 nM; <b>TK-685</b>: SHP2^WT IC₅₀ = 1.5 nM; <i>K</i>_<i>i</i> = 0.87 nM), likely binding to the "tunnel" allosteric site of SHP2. By targeting SHP2-mediated AKT and ERK signaling pathways, <b>TK-684</b> and <b>TK-685</b> suppressed cell proliferation and induced apoptosis in esophageal cancer cells. Additionally, oral administration of <b>TK-685</b> demonstrated good antitumor effects in the KYSE-150 xenograft mouse model, with a T/C value of 76.8%. Collectively, the pyrazolopyrimidinone derivatives represent promising lead compounds for the treatment of esophageal cancer, where SHP2 is dysregulated.