The development of a synthetic small molecule that can regulate the oxidative-stress response transcriptional network is thought to be of therapeutic value. This concept is particularly interesting if the molecule acts upon the NRF2 pathway, which regulates the anti-oxidant response element (ARE) genes.  To date, however, this approach has relied on pharmacophores having reactive, electrophilic groups which may present safety and tolerability issues.  vTv Therapeutics has identified multiple classes of novel non-electrophilic small molecules that can modulate/activate both NRF2 and Bach1 (the ARE transcriptional repressor) leading to potent activation of the NRF2 pathway. 

Over 200 anti-oxidant and cytoprotective genes are reported to be regulated by NRF2.  Activation of the NRF2 pathway not only relieves oxidative stress but also controls inflammatory responses, preventing tissue damage.  Modulation of the NRF2/Bach1 pathway by our compounds in vitro and in vivo shows suppression of both oxidative stress and inflammation by increasing anti-oxidant proteins, increasing cellular glutathione levels, increasing anti-inflammatory cytokine production, inhibiting NFκB transcriptional activity, and enhancing macrophages towards the anti-inflammatory “M2” phenotype. 

Published data suggest that small molecules that function as modulators of NRF2/Bach1 pathway may have therapeutic benefit in acute indications such as radiation protection in cancer patients, protection against contrast-induced renal injury, and prevention of ischemia/reperfusion injury, as well as a variety of chronic indications including respiratory injuries, neurodegenerative diseases, and mitochondrial myopathies.