Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors

Inhibition of the protein–protein interaction
between Kelch-like
ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related
factor 2 (Nrf2) has been recognized as an attractive approach for
treating oxidative stress-related diseases. Here, we present a new
series of noncovalent Keap1-Nrf2 inhibitors developed by a conformational
restriction strategy of our fluorenone-based compounds previously
identified by fragment-based drug discovery. The design was guided
by X-ray cocrystal structures, and the subsequent optimization process
aimed at improving affinity, cellular activity, and metabolic stability.
From the noncyclic compound 7 (Ki = 2.9 μM), a new series of tetrahydroisoquinoline-based
Keap1 inhibitors with up to 223-fold improvement in binding affinity
(57, Ki = 13 nM), better
metabolic stability, and enhanced cellular activity was obtained.
In addition, the compounds showed selectivity for the Keap1 Kelch
domain across a panel of 15 homologous proteins. We thereby demonstrate
the utility of cyclic rigidification in the design of potent and more
drug-like Keap1-Nrf2 inhibitors.