4 research outputs found
Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and XāLinked Inhibitor of Apoptosis Protein (XIAP)
XIAP and cIAP1 are
members of the inhibitor of apoptosis protein
(IAP) family and are key regulators of anti-apoptotic and pro-survival
signaling pathways. Overexpression of IAPs occurs in various cancers
and has been associated with tumor progression and resistance to treatment.
Structure-based drug design (SBDD) guided by structural information
from X-ray crystallography, computational studies, and NMR solution
conformational analysis was successfully applied to a fragment-derived
lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist
of XIAP and cIAP1 and a structurally novel chemical probe for IAP
biology
Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 ProteināProtein Interaction
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2āRelated Factor 2 (KEAP1:NRF2) ProteināProtein 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
KelchāNRF2 interaction. X-ray crystallographic screening identified
three distinct āhot-spotsā 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 KEAP1āNRF2 interaction