Development of Potent SHP2 Allosteric Inhibitors: Design, Synthesis, and Evaluation with Antitumor Effects

Src homology-2-containing protein tyrosine phosphatase (PTP) 2 (SHP2) is a pivotal PTP that modulates key cellular processes including proliferation, differentiation, and migration. Its overexpression is implicated in the pathogenesis of various malignancies, highlighting the need for effective SHP2 inhibitors. Herein, we report the design and synthesis of a novel series of thiazolo[5,4-<i>b</i>]pyridine and imidazo[1,2-<i>c</i>]pyrimidine derivatives as SHP2 allosteric inhibitors identified through active fragment splicing. The synthesized compounds exhibited potent SHP2 inhibition, with IC₅₀ values ranging from 9.0 to 34.5 nM. Notably, compound <b>B8</b> demonstrated superior potency, with an IC₅₀ of 0.04 μM for p-ERK modulation. Compound <b>B8</b> also displayed favorable drug-like properties and significant antitumor activity in a KYSE520 xenograft mouse model, underscoring its potential as a lead candidate for further development. Our findings provide a foundation for the advancement of SHP2-targeted therapeutics.