Overview
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.
Clinical Trials
First generation compound, HPP971, has completed two phase 1 studies where it was well tolerated.
Mechanism of Action
Activation of the NRF2 pathway not only relieves oxidative stress but also controls inflammatory responses, preventing tissue damage. To date, however, this approach has relied on molecules having reactive, electrophilic groups which may present safety and tolerability issues.
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.
Publications
Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics
- Wada S, Kanzaki H, Katsumata Y, Yamaguchi Y, Narimiya T, Attucks O, Nakamura Y, Tomonari H. Bach1 Inhibition Suppresses Osteoclastogenesis via Reduction of the Signaling via Reactive Oxygen Species by Reinforced Antioxidation.Frontiers in Cell and Developmental Biology, VOLUME 8. August 2020
- Cuadrado, A; Rojo, A; Wells, G; Hayes, J; Cousin, S; Rumsey, W; Attucks, O; Franklin, S; Levonen, A-L; Kensler, T; Dinkova-Kostova, A. Therapeutic targeting of Nrf2 and Keap1 partnership in chronic diseases. Nature Reviews Drug Discovery 2018
- Attucks, OC, Jasmer, KJ, Hannink, M, Kassis, J, Zhong, Z, Gupta, S, Victory, SF, Guzel, M, Polisetti, DR, Andrews, R, Mjalli, AMM, Kostura, MJ. A novel class of compounds induce heme oxygenase I (HMOX1) through modulation of Bach1 activity. PLOS one July 12, 2014
Presentations and Posters
Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics
- Sung-Kwon Kim, Jareer Kassis, Otis Attucks, Zhenping Zhong , Jennifer Freeman, Suparna Gupta, Sam Victory, Dharma Polisetti, Adnan Mjalli, Rob Andrews, Matt Kostura, Mustafa Guzel, Bapu Gaddam, Shawnee Weaver, Kate Sakmann and Stephen Davis. The novel Bach1 inhibitor HPP971 uniquely activates Nrf2 and reduces disease severity in a mouse model of experimental autoimmune encephalomyelitis. ACTRIMS-ECTRIMS Meeting 2014
- Attucks O. and Valcarce C. Non-electrophilic activation of the Nrf2 pathway ameliorated experimental Nonalcoholic Steatohepatitis. Presented at the EASL Non-Alcoholic Fatty Liver Disease (NAFLD) Summit 2019, September 28, 2019, Seville, Spain