4 research outputs found
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
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
Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2
Aberrant activation of the MAPK pathway
drives cell proliferation
in multiple cancers. Inhibitors of BRAF and MEK kinases are approved
for the treatment of BRAF mutant melanoma, but resistance frequently
emerges, often mediated by increased signaling through ERK1/2. Here,
we describe the fragment-based generation of ERK1/2 inhibitors that
block catalytic phosphorylation of downstream substrates such as RSK
but also modulate phosphorylation of ERK1/2 by MEK without directly
inhibiting MEK. X-ray crystallographic and biophysical fragment screening
followed by structure-guided optimization and growth from the hinge
into a pocket proximal to the C-α helix afforded highly potent
ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant
cells, the lead compound suppresses pRSK and pERK levels and inhibits
proliferation at low nanomolar concentrations. The lead exhibits tumor
regression upon oral dosing in BRAF mutant xenograft models, providing
a promising basis for further optimization toward clinical pERK1/2
modulating ERK1/2 inhibitors
Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2
Aberrant activation of the MAPK pathway
drives cell proliferation
in multiple cancers. Inhibitors of BRAF and MEK kinases are approved
for the treatment of BRAF mutant melanoma, but resistance frequently
emerges, often mediated by increased signaling through ERK1/2. Here,
we describe the fragment-based generation of ERK1/2 inhibitors that
block catalytic phosphorylation of downstream substrates such as RSK
but also modulate phosphorylation of ERK1/2 by MEK without directly
inhibiting MEK. X-ray crystallographic and biophysical fragment screening
followed by structure-guided optimization and growth from the hinge
into a pocket proximal to the C-α helix afforded highly potent
ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant
cells, the lead compound suppresses pRSK and pERK levels and inhibits
proliferation at low nanomolar concentrations. The lead exhibits tumor
regression upon oral dosing in BRAF mutant xenograft models, providing
a promising basis for further optimization toward clinical pERK1/2
modulating ERK1/2 inhibitors