1 research outputs found
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 <i>PTPN11</i> 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)Âpyrazin-2-amine
(SHP099, <b>1</b>), a potent, selective, orally bioavailable,
and efficacious SHP2 inhibitor