Bardoxolone Methyl

Chemical structure:

Chemical name: Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate

Indication: Bardoxolone methyl is an Antioxidant Inflammation Modulators (AIMs) indicated for the treatment of advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients.

Side effects : The most frequently reported adverse event in the bardoxolone methyl was muscle spasm.

Role of Nrf2:

Nrf2 (the transcription factor nuclear factor erythroid 2-related factor 2) is the regulator of the oxidative/electrophilic stress response.

Nrf2 regulates the synthesis of glutathione (GSH).

Its turnover is maintained by Keap1 via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form a hinge and latch. Keap1 recognizes Nrf2 through its conserved ETGE and DLG motifs within the regulatory Neh2 domain of Nrf2.

(A)Schematic diagram showing the two-site substrate recognition model. Keap1 is composed of BTB (yellow ovals), intervening region (IVR) (light violet bars), and DGR/CTR (Keap1-DC; green hexagons) domains. Keap1 homodimer binds with one Neh2 domain (magenta hockey stick) of Nrf2. The multiple ubiquitin (Ub) units are shown as red ovals. Neh2 binds to Keap1 DC via both the ETGE and DLG motifs under unstressed conditions. This complex configuration facilitates efficient ubiquitination of the lysines in Neh2.

(B) mimics conditions of oxidative stress. The DLG motif, therefore, acts as a latch to lock and unlock the lysines of Neh2 in an appropriate spatial orientation for targeting ubiquitin transfer by the E2 enzyme in different cellular redox state

BARD regulates various proteins regarding inflammation and carcinogenesis by reversible Michael addition between cyano enone in ring A of BARD and the SH

groups of cysteine moieties on Keap1 protein (cysteine residues (C151, C273 ,and C288) in the intervening region of Keap1.