Chemoproteomic-enabled identification of covalent modulators of KEAP1

The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) plays a critical role in maintaining cellular homeostasis by regulating the expression of numerous gene products which counter oxidative stress, promote cellular detoxification and by suppressing the expression of pro-inflammatory genes. Under normal conditions, cellular levels of NRF2 are maintained at a low level by the actions of a CUL3-based E3 ligase, Kelch-like ECH-associated protein 1 (KEAP1), which targets NRF2 for ubiquitination and proteosomal degradation. Employing an industrialized chemoproteomic platform, we have identified and optimized the potency, selectivity and ADME properties of a series of covalent beta-chloroacrylamide containing inhibitors of KEAP1 which engage Cys 151, resulting in the nuclear accumulation of NRF2. The relationship of PK to PD and target engagement as well as efficacy in an animal model of IBD after oral administration of an advanced lead compound will be discussed.