SHP2-targeted cancer therapeutics: Structural insights, inhibitor development and emerging modalities

Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a ubiquitously expressed non-receptor protein tyrosine phosphatase that functions as a central signaling hub in multiple oncogenic pathways, including RAS-RAF-ERK, PI3K-AKT and JAK-STAT cascades. As a prototypical proto-oncoprotein of the protein tyrosine phosphatase family, SHP2 has been causally implicated in malignant transformation, tumor progression, metastatic dissemination and acquired therapeutic resistance, highlighting its significance as a compelling therapeutic target in oncology. Traditional SHP2 inhibitor development targeting the conserved catalytic domain was constrained by poor selectivity and limited drug-likeness properties. The identification of a druggable allosteric pocket represented a paradigm shift, enabling rapid development of highly selective allosteric inhibitors, several of which have advanced into clinical trials. Complementary approaches, including protein-protein interaction inhibitors, dual-target agents and other event-driven modalities such as targeted protein degradation, are expanding the mechanistic repertoire of SHP2-targeted intervention and offering new opportunities to enhance therapeutic efficacy and overcome adaptive resistance. This review provides a comprehensive overview of the structural and functional characteristics of SHP2, its multifaceted roles in cancer biology, the evolution of inhibitor design strategies and emerging therapeutic modalities. Critical challenges and future perspectives are also discussed to inform the rational development and clinical translation of next-generation SHP2-targeted therapies.