Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase‑2 (SHP2)

The ubiquitously expressed protein
tyrosine phosphatase
SHP2 is
required for signaling downstream of receptor tyrosine kinases (RTKs)
and plays a role in regulating many cellular processes. Genetic knockdown
and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling
and inhibit the proliferation of RTK-driven cancer cell lines. Here,
we describe the first reported fragment-to-lead campaign against SHP2,
where X-ray crystallography and biophysical techniques were used to
identify fragments binding to multiple sites on SHP2. Structure-guided
optimization, including several computational methods, led to the
discovery of two structurally distinct series of SHP2 inhibitors binding
to the previously reported allosteric tunnel binding site (Tunnel
Site). One of these series was advanced to a low-nanomolar lead that
inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts.
Furthermore, a third series of SHP2 inhibitors was discovered binding
to a previously unreported site, lying at the interface of the C-terminal
SH2 and catalytic domains.