Human Kelch-like ECH Associated Protein 1 (KEAP1); A Target Enabling Package

<p>KEAP1 is a highly redox-sensitive member of the BTB-Kelch family that assembles with the CUL3 protein to form a Cullin-RING E3 ligase complex for the degradation of NRF2. Oxidative stress disables KEAP1 allowing NRF2 protein levels to accumulate for the transactivation of critical stress response genes. Consequently, the KEAP1-NRF2 system is a highly attractive target for the development of protein-protein interaction inhibitors that will stabilise NRF2 for therapeutic effect in conditions of neurodegeneration and inflammation. As part of this TEP we have solved the first crystal structure of a KEAP1-CUL3 complex as well as a structure of the apo-Kelch domain suitable for small molecule soaking. We further established a selectivity assay panel of 17 human Kelch domain-containing proteins and have shown that non-covalent KEAP1 inhibitors from the literature are highly selective for KEAP1. This protein panel offers a resource for future work on KEAP1 as well as 16 other human Kelch proteins.</p>