Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

SHP2
is a nonreceptor protein tyrosine phosphatase within the mitogen-activated
protein kinase (MAPK) pathway controlling cell growth, differentiation,
and oncogenic transformation. SHP2 also participates in the programed
cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule
inhibition of SHP2 has been widely investigated, including in our
previous reports describing SHP099 (2), which binds to a tunnel-like
allosteric binding site. To broaden our approach to allosteric inhibition
of SHP2, we conducted additional hit finding, evaluation, and structure-based
scaffold morphing. These studies, reported here in the first of two
papers, led to the identification of multiple 5,6-fused bicyclic scaffolds
that bind to the same allosteric tunnel as 2. We demonstrate the structural
diversity permitted by the tunnel pharmacophore and culminated in
the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that
modulate MAPK signaling in vivo. These studies also served as the
basis for further scaffold morphing and optimization, detailed in
the following manuscript.