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.

Alessia Petrocchi ¹, Alessandro Grillo ², Luca Ferrante ², Pietro Randazzo ², Adolfo Prandi ², Marilenia De Matteo ², Costanza Iaccarino ¹, Monica Bisbocci ¹, Antonella Cellucci ¹, Cristina Alli ¹, Martina Nibbio ¹, Vincenzo Pucci ¹, Jérôme Amaudrut ¹, Christian Montalbetti ¹, Carlo Toniatti ¹, Romano Di Fabio ¹ ²

Affiliations

1 IRBM S.p.A, Via Pontina Km 30.600, 00070 Pomezia, Italy.
2 Promidis, Via Olgettina 60, 20132 Milano, Italy.

PMID: 37197453 DOI: 10.1021/acsmedchemlett.3c00059

Abstract

Src homology 2-containing protein tyrosine Phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine Phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.

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