Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer

SHP2 is a nonreceptor protein tyrosine
phosphatase encoded by the PTPN11 gene and is involved
in cell growth and differentiation
via the MAPK signaling pathway. SHP2 also plays an important role
in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein
as well as a potential immunomodulator, controlling SHP2 activity
is of high therapeutic interest. As part of our comprehensive program
targeting SHP2, we identified multiple allosteric binding modes of
inhibition and optimized numerous chemical scaffolds in parallel.
In this drug annotation report, we detail the identification and optimization
of the pyrazine class of allosteric SHP2 inhibitors. Structure and
property based drug design enabled the identification of protein–ligand
interactions, potent cellular inhibition, control of physicochemical,
pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of
TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)­thio)­pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro­[4.5]­decan-4-amine
(1), a highly potent, selective, orally efficacious,
and first-in-class SHP2 inhibitor currently in clinical trials for
cancer.