Structure–Activity and Structure–Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2‑Related Factor 2 (KEAP1/NRF2) Protein–Protein Interaction

The KEAP1–NRF2-mediated
cytoprotective response plays a
key role in cellular homoeostasis. Insufficient NRF2 signaling during
chronic oxidative stress may be associated with the pathophysiology
of several diseases with an inflammatory component, and pathway activation
through direct modulation of the KEAP1–NRF2 protein–protein
interaction is being increasingly explored as a potential therapeutic
strategy. Nevertheless, the physicochemical nature of the KEAP1–NRF2
interface suggests that achieving high affinity for a cell-penetrant
druglike inhibitor might be challenging. We recently reported the
discovery of a highly potent tool compound which was used to probe
the biology associated with directly disrupting the interaction of
NRF2 with the KEAP1 Kelch domain. We now present a detailed account
of the medicinal chemistry campaign leading to this molecule, which
included exploration and optimization of protein–ligand interactions
in three energetic “hot spots” identified by fragment
screening. In particular, we also discuss how consideration of ligand
conformational stabilization was important to its development and
present evidence for preorganization of the lead compound which may
contribute to its high affinity and cellular activity.