Therapeutic potential of targeting SHP2 in human developmental disorders and cancers

Abstract

Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, regulates cell proliferation, differentiation, apoptosis and survival via releasing intramolecular autoinhibition and modulating various signaling pathways, such as mitogen-activated protein kinase (MAPK) pathway. Mutations and aberrant expression of SHP2 are implicated in human developmental disorders, leukemias and several solid tumors. As an oncoprotein in some cancers, SHP2 represents a rational target for inhibitors to interfere. Nevertheless, its tumor suppressive effect has also been uncovered, indicating the context-specificity. Even so, two types of SHP2 inhibitors including targeting catalytic pocket and allosteric sites have been developed associated with resolved cocrystal complexes. Herein, we describe its structure, biological function, deregulation in human diseases and summarize recent advance in development of SHP2 inhibitors, trying to give an insight into the therapeutic potential in future.

Keywords: Allosteric site; Cancer; Catalytic pocket; Developmental disorder; SHP2 inhibitor.