Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

Abstract

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA-approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non-specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy.

Keywords: Nrf2; bach1; ferroptosis; neurodegeneration; neurotherapeutics.

Figure. 1.

Regulation of Nrf2/Bach1 signaling. Dimeric Keap1 protein, the adapter in ubiquitin ligase complex, stretches the N-terminal domain of Nrf2, Neh2, by interacting with DLG (weak) and ETGE (strong) binding motifs in Neh2 domain to expose Neh2 lysine residues (shown in green dots) for ubiquitination. This modification targets the Nrf2 protein for proteasomal degradation. Keap1 is a redox sensor with multiple cysteine residues (shown in yellow dots), which, being oxidized or modified, compromise either Keap1 dimeric structure or its binding to ubiquitin ligase, leading to Nrf2 protein release and translocation to the nucleus. Displacement activators competitively substitute Nrf2 without covalent modification of Keap1. A big portion of Nrf2 target genes is blocked from expression because of the repression from the Bach1-Maf protein complex occupying ARE sites. Upon Bach1 interaction with Bach1 inhibitors targeting the Bach1 heme-binding domain (shown as a red dot), Bach1 exits the nucleus and is subjected to proteasomal degradation, whereas Nrf2, in turn, binds Maf coactivator and activates the expression of cytoprotective genes regulated by Nrf2/Bach1 interplay.

Figure. 2.

General formula of fused benzimidazole series of Bach1 inhibitors showing the tested substitutions in Mitobridge patent in positions for R1 and R2. OCF3 in benzo[d]thiazole is equally good to a CF3 substituted variant with respect to Bach1 inhibition activity. R1 and R2 substituents’ volume and length are interdependent for the maximum activity (see text for details).

Figure. 3.

Bach1 inhibitors described in the literature. A, HPPE, the best inhibitor in fused benzimidazole series resembles the structure of hemin, a physiological inhibitor of Bach1; B, attachment of biotin (bicycle ring on the right) to Nrf2 activator TBE31 (fused tricycle on the left) makes a potent Bach1 inhibitor, TBE56; C, CBD, a Bach1 inhibitor, modified with a para-quinone motif, becomes an Nrf2 activator as well.

Figure. 4.

Domain structures of Keap1 and Bach1 showing the cysteine residues modified by dimethyl fumarate by blue arrows (based on our results in [39]). Keap1 contains 22 cysteine residues. Cys151 (purple bar) is covalently modified by dimethyl fumarate and is located at the interface of Keap1 and ubiquitin ligase. Bach1 contains 6 CP-motifs (red bars), but only CP6 is implicated in forming a 5-coordinated heme. Five cysteine residues are modified in Bach1, with Cys649 in CP6, responsible for heme-binding to warrant Bach1 exit from the nucleus.