K-181 is a specific small-molecule Protein-Protein Interaction (PPI) inhibitor of Mdmx-p53 interaction, exhibits neuroprotective effects on ischemic stroke by disrupting Mdmx-p53 interaction and inhibiting HDAC6 activity.
K-181 preferentially inhibited Mdmx-p53 interaction over Mdm2-p53 interaction and suppressed the growth of cancer cells.
K-181 could be hydrolyzed to its free thiol derivative (K-181SH) in cells, interfered with the p53-Mdmx interaction through disulfide-bond formation between the free thiol groups of K-181SH and Cys77 in Mdmx in the p53-binding domain.
K-181 (50 mg/kg/day, oral) increased Mdmx expression in mice brain under physiological condition.
K-181 attenuated acute ischemic stroke damage in mice, increased Mdmx expression under ischemic stroke in both in vivo and in vitro.
K-181 exerted neuroprotective effects in response to hypoxia/reperfusion in neurons.
K-181 selectively inhibited HDAC6 activity and enhanced tubulin acetylation.