Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

Abstract

Oxidative stress has been implicated in a wide range of pathological conditions. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a central role in regulating the cellular defense system against oxidative and electrophilic insults. Nonelectrophilic inhibition of the protein−protein interaction (PPI) between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 has become a promising approach to activate Nrf2. Recently, multiple drug discovery strategies have facilitated the development of small-molecule Keap1−Nrf2 PPI inhibitors with potent activity and favorable drug-like properties. In this Perspective, we summarize the latest progress of small-molecule Keap1−Nrf2 PPI inhibitors from medicinal chemistry insights and discuss future prospects and challenges in this field.

Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein–Protein Interaction Inhibitors

“…As another type of Nrf2 activator, noncovalent inhibitors of Keap1-Nrf2 protein–protein interaction (PPI) have attracted attention as lower risk agents for antioxidant therapy (Figure b). , Although many studies for noncovalent Keap1-Nrf2 inhibitors have been conducted, no clinical candidate has been reported to date. To our knowledge, most of reported noncovalent compounds seem to exhibit limited physicochemical properties such as low aqueous solubility, metabolic stability, or membrane permeability, resulting in unsatisfactory bioavailability ( F ) and high in vivo clearance. ,, These results are likely due to the characteristics of the Nrf2 binding site (550–780 Å 2 ) that is relatively large and has multiple polar residues including Arg 380, Arg 415, and Arg 483, which generally tend to bind to ligands with high molecular weight and polar surface area (PSA).…”