Shi Cheng, Zhao Yanping, Huang Han, Zhou Jiaxu, Lu Dehua, Chen Yanming, Lyu Weiping, Liu Zhenming, Wang Hongjun, Zhang Liangren
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Beijing Tide Pharmaceutical Co., Ltd., Beijing 100176, China.
J Med Chem. 2025 Mar 13;68(5):5238-5256. doi: 10.1021/acs.jmedchem.4c02100. Epub 2025 Mar 4.
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-]pyridine and imidazo[1,2-]pyrimidine derivatives as SHP2 allosteric inhibitors identified through active fragment splicing. The synthesized compounds exhibited potent SHP2 inhibition, with IC values ranging from 9.0 to 34.5 nM. Notably, compound demonstrated superior potency, with an IC of 0.04 μM for p-ERK modulation. Compound 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）是一种关键的蛋白酪氨酸磷酸酶，可调节包括增殖、分化和迁移在内的关键细胞过程。其过表达与多种恶性肿瘤的发病机制有关，这凸显了对有效SHP2抑制剂的需求。在此，我们报告了一系列新型噻唑并[5,4 -]吡啶和咪唑并[1,2 -]嘧啶衍生物的设计与合成，这些衍生物作为通过活性片段拼接鉴定出的SHP2变构抑制剂。合成的化合物表现出强效的SHP2抑制作用，IC值范围为9.0至34.5 nM。值得注意的是，化合物 表现出卓越的效力，对p - ERK调节的IC为0.04 μM。化合物 在KYSE520异种移植小鼠模型中还表现出良好的类药性质和显著的抗肿瘤活性，强调了其作为进一步开发的先导候选物的潜力。我们的研究结果为SHP2靶向治疗药物的发展奠定了基础。
