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

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. The Nrf2 activator stabilizes Nrf2. Nrf2 outcompetes Bach1 to bind to the ARE site. Bach1 inhibitor causes Bach1 exit from the nucleus, Nrf2 is de-repressed and activates transcription of cytoprotective and antioxidant genes, including HMOX1. HMOX1 degrades heme, the physiological inhibitor of Bach1 protein stabilization. Bach1 inhibitor counteracts feedback upregulation of Bach1 protein, resulting in full-scale activation of the Nrf2-driven genetic program.image