4 research outputs found
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2‑Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery
KEAP1
is the key regulator of the NRF2-mediated cytoprotective
response, and increasingly recognized as a target for diseases involving
oxidative stress. Pharmacological intervention has focused on molecules
that decrease NRF2-ubiquitination through covalent modification of
KEAP1 cysteine residues, but such electrophilic compounds lack selectivity
and may be associated with off-target toxicity. We report here the
first use of a fragment-based approach to directly target the KEAP1
Kelch–NRF2 interaction. X-ray crystallographic screening identified
three distinct “hot-spots” for fragment binding within
the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment
hit to molecules with nanomolar affinity for KEAP1 while maintaining
drug-like properties. This work resulted in a promising lead compound
which exhibits tight and selective binding to KEAP1, and activates
the NRF2 antioxidant response in cellular and <i>in vivo</i> models, thereby providing a high quality chemical probe to explore
the therapeutic potential of disrupting the KEAP1–NRF2 interaction
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