俞鐘山 教授    李靜琪 研究員

　　Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2), encoded by the PTPN11 gene, plays a critical role in regulating diverse cellular signaling pathways involved in cell growth, differentiation, metabolism, and migration. Dysregulation of SHP2 has been implicated in the development of various hematological and solid tumors and has also been associated with resistance to anticancer therapies, making SHP2 an attractive therapeutic target for cancer treatment.

In this study, novel SHP2 inhibitors have been explored through small-molecule library screening, substructure searches of in-house compound libraries, rational drug design, and virtual screening. Based on the results obtained, three series of compounds featuring pyrimidine, pyrazine, and imidazo[1,2-b]pyridazine scaffolds were designed and synthesized. Subsequent optimization identified compounds bearing a 2-phenyl-imidazo[1,2-b]pyridazine scaffold with improved inhibitory activity against SHP2. Building on these findings, further structural optimization and structure–activity relationship studies will be conducted to identify more potent SHP2 inhibitors and explore their potential as anticancer agents.