Petrocchi, A., & Ciammaichella, A. (2024). A patent review of SHP2 allosteric inhibitors (2018-present). Expert Opinion on Therapeutic Patents, 34(5), 383–396. https://doi.org/10.1080/13543776.2024.2365410

The presence of over 100 patents on SHP2 inhibitors underscores the target’s importance and potential impact in drug discovery and therapeutic applications in oncology. Our resident experts, Alessia Petrocchi and Alina Ciammaichella have published a comprehensive review on the topic.

Introduction
SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) has emerged as a promising target for cancer therapy due to its pivotal role in regulating the RAS/MAPK signaling pathway downstream of receptor tyrosine kinases (RTKs). Additionally, SHP2 contributes to immune evasion by inhibiting T cells through the PD-1/PD-L1 pathway. This phosphatase is essential in various physiological and pathological processes, including cell proliferation, survival, and migration, making it a critical focus for therapeutic development.

Areas Covered
This review delves into recent advancements in SHP2 allosteric inhibitors, specifically those disclosed in patents published between 2018 and the present in Espacenet and SciFinder databases. The analysis highlights structural innovations in these inhibitors, with particular emphasis on modifications made to SHP099, the first allosteric inhibitor of SHP2 ever described.

Expert Opinion
Significant progress has been made in the discovery and preclinical testing of potent SHP2 allosteric inhibitors, many of which demonstrate promising efficacy in cancer models. Currently, 15 compounds are undergoing clinical development; however, none have yet received market approval. Long-term efficacy as monotherapy remains a challenge due to resistance mechanisms and limited standalone effectiveness. Nonetheless, combination therapies—partnering SHP2 inhibitors with agents targeting MEK, BRAF, EGFR, RAS-G12C, or PD-L1—hold tremendous potential and represent a rapidly expanding area of research in oncology.