Petrocchi A, Grillo A, Ferrante L, Randazzo P, Prandi A, De Matteo M, Iaccarino C, Bisbocci M, Cellucci A, Alli C, Nibbio M, Pucci V, Amaudrut J, Montalbetti C, Toniatti C, Di Fabio R. Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors. ACS Med Chem Lett. 2023 Apr 17;14(5):645-651. doi: 10.1021/acsmedchemlett.3c00059. PMID: 37197453; PMCID: PMC10184159.

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first known nonreceptor oncogenic tyrosine phosphatase, playing a pivotal role in signal transduction cascades and mediating immunoinhibitory functions via the PD-1 checkpoint receptor. In pursuit of novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives were developed, incorporating a unique bicyclo[3.1.0]hexane moiety in the left-hand region of the molecule.

This study highlights the discovery process, the in vitro pharmacological profile, and the early developability characteristics of compound 25, a standout candidate in this series due to its high potency. The findings provide valuable insights into the development of innovative therapies targeting SHP2 for cancer treatment and immunotherapy.