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-b]­pyridine and imidazo­[1,2-c]­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 B8 demonstrated superior potency, with an IC50 of 0.04 μM for p-ERK modulation. Compound B8 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.

含Src同源2结构域的蛋白酪氨酸磷酸酶（PTP）2（SHP2）是一类关键的蛋白酪氨酸磷酸酶，可调控细胞增殖、分化与迁移等核心细胞过程。该酶的过表达与多种恶性肿瘤的发病机制紧密相关，因此开发高效的SHP2抑制剂具有重要研究价值。本研究报道了通过活性片段拼接技术筛选得到的新型噻唑并[5,4-b]吡啶与咪唑并[1,2-c]嘧啶衍生物系列的设计与合成。所合成的化合物均展现出强效的SHP2抑制活性，半数抑制浓度（IC50）范围为9.0~34.5 nM。其中化合物B8的活性尤为突出，其调控p-ERK的IC50可达0.04 μM。此外，化合物B8具备良好的成药性，并在KYSE520细胞异种移植小鼠模型中展现出显著的抗肿瘤活性，凸显其作为候选先导化合物进行后续开发的巨大潜力。本研究成果为靶向SHP2的治疗药物研发奠定了坚实基础。