Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

SHP2
is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation
via the MAPK signaling pathway. SHP2 also purportedly plays an important
role in the programmed cell death pathway (PD-1/PD-L1). Because it
is an oncoprotein associated with multiple cancer-related diseases,
as well as a potential immunomodulator, controlling SHP2 activity
is of significant therapeutic interest. Recently in our laboratories,
a small molecule inhibitor of SHP2 was identified as an allosteric
modulator that stabilizes the autoinhibited conformation of SHP2.
A high throughput screen was performed to identify progressable chemical
matter, and X-ray crystallography revealed the location of binding
in a previously undisclosed allosteric binding pocket. Structure-based
drug design was employed to optimize for SHP2 inhibition, and several
new protein–ligand interactions were characterized. These studies
culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)­pyrazin-2-amine
(SHP099, 1), a potent, selective, orally bioavailable,
and efficacious SHP2 inhibitor.