CBR-470-1 is a small molecule inhibitor of glycolytic enzyme phosphoglycerate kinase 1 (PGK1), activates NRF2 signaling in vitro and in vivo. CBR-470-1 induces transcript levels of NQO1 and HMOX1, as well as enhances NRF2 protein stabilization in HEK293T, SH-SY5Y, and primary human lung fibroblasts. CBR-470-1 induces methylglyoxal modification of Keap1, Keap1-Nrf2 disassociation, and increases expression of Nrf2 responsive genes. CBR-470-1 potently attenuates MPP+-induced oxidative injury and SH-SY5Y cell apoptosis. CBR-470-1 neuroprotection is dependent upon Nrf2, as Nrf2 shRNA or CRISPR/Cas9-mediated Nrf2 knockout, abolished CBR-470-1-induced SH-SY5Y cytoprotection against MPP+.
