Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors

Abstract

Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the Ptpn11 gene, which regulates cell growth, differentiation and apoptosis via modulating various signaling pathways, such as the RAS/ERK signaling pathway, and participates in the PD-1/PD-L1 pathway governing immune surveillance. It has been recognized as a breakthrough antitumor therapeutic target. Besides, numerous studies have shown that SHP2 plays an important role in the regulation of inflammatory diseases. However, inhibitors targeting the active site of SHP2 lack drug-likeness due to their low selectivity and poor bioavailability, thus none has advanced to clinical development. Recently, allosteric inhibitors that stabilize the inactive conformation of SHP2 have achieved breakthrough progress, providing the clinical proof for the druggability of SHP2 as an antitumor drug target. This paper reviews the recently reported design and discovery of SHP2 small molecule inhibitors, focused on the structure-activity relationship (SAR) analysis of several representative SHP2 inhibitors, outlining the evolution and therapeutic potential of the small molecule inhibitors targeting SHP2.

Fig. 1. Schematic illustration of the activation of SHP2 by the binding of SH2 domains with the tyrosine phosphorylated proteins or mutations in N-SH2 and PTP domains.

Fig. 2. Schematic SHP2-mediated main signaling pathways: 1) SHP2-associated growth factor dependent signalling pathways, including RAS/Raf/ERK and PI3K/AKT pathway, and 2) SHP2 inhibiting T cell activation through PD-L1/PD-1 mediated ITIM and ITSM signalling.

Fig. 3. SHP2 inhibitors targeting the catalytic pocket of the enzyme.

Fig. 4. Representative SHP2 inhibitors targeting the allosteric sites.

Jiao Kong

Ya-Qiu Long