KEAP1

Kelch-like ECH-associated protein 1 is a is_associated_with::protein that in humans is encoded by the Keap1 is_associated_with::gene.

Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region (CTR) domains collaborate to form a is_associated_with::β-propeller structure, which is where Keap1 interacts with is_associated_with::Nrf2.

Interactions
Keap1 has been shown to interact with: is_associated_with::Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of and is_associated_with::oxidative stress.

Under quiescent conditions, is_associated_with::Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the is_associated_with::ubiquitination and subsequent is_associated_with::proteolysis of is_associated_with::Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on is_associated_with::Nrf2.

As a Drug Target
Because Nrf2 activation leads to a coordinated is_associated_with::antioxidant and is_associated_with::anti-inflammatory response, and Keap1 represses is_associated_with::Nrf2 activation, Keap1 has become a very attractive drug target.

A series of synthetic oleane is_associated_with::triterpenoid compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-is_associated_with::Nrf2 pathway, blocking Keap1-dependent is_associated_with::Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of is_associated_with::Nrf2 and subsequent induction of Nrf2 target genes.) The lead compound in this series, is_associated_with::bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of is_associated_with::chronic kidney disease (CKD) in patients with type 2 is_associated_with::diabetes mellitus and showed an ability to improve markers of renal function in these patients.) However, the Phase 3 trial was halted due to safety concerns.