Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

The NRF2-mediated cytoprotective
response is central to cellular
homoeostasis, and there is increasing interest in developing small-molecule
activators of this pathway as therapeutics for diseases involving
chronic oxidative stress. The protein KEAP1, which regulates NRF2,
is a key point for pharmacological intervention, and we recently described
the use of fragment-based drug discovery to develop a tool compound
that directly disrupts the protein−protein interaction between
NRF2 and KEAP1. We now present the identification of a second, chemically
distinct series of KEAP1 inhibitors, which provided an alternative
chemotype for lead optimization. Pharmacophoric information from our
original fragment screen was used to identify new hit matter through
database searching and to evolve this into a new lead with high target
affinity and cell-based activity. We highlight how knowledge obtained
from fragment-based approaches can be used to focus additional screening
campaigns in order to de-risk projects through the rapid identification
of novel chemical series.