CAST-calpain-2 stabilizer-1

CAST-calpain-2 stabilizer-1 is a stabilizing agent that can penetrate the blood-brain barrier, interacting specifically with CAST-calpain-2. It shows no activity towards GSK3. This compound is useful for research in Huntington's disease and tauopathies.

CAST-calpain-2 stabilizer-1 (A36) effectively restores mitochondrial membrane potential in striatal neuron-like cells from HdhQ111 mice with an EC₅₀ of 2.77 μM and improves cell viability with an EC₅₀ of 1.55 μM. It elevates CAST protein expression in these cells at an EC₅₀ of approximately 3.55 μM and reduces mitochondrial ROS production with an IC₅₀ of approximately 1.43 μM. CAST-calpain-2 stabilizer-1 enhances the endogenous interaction between CAST and calpain-2 in HdhQ111 striatal neuron-like cells. At concentrations of 0-500 μM for 40 minutes, it binds directly and stabilizes CAST protein in a dose-dependent manner in cell lysates. Mitochondrial protective effects and improved cell viability require endogenous CAST and calpain-2 at concentrations of 5-10 μM over 48 hours. Moreover, at 1 μM for 5 days, it restores neuronal marker expression, inhibits calpain-2 activity, and rescues axonal growth in medium spiny neurons derived from human patient iPSC Huntington's disease (HD).

CAST-calpain-2 stabilizer-1 (A36) administered intraperitoneally at a dose of 10 mg/kg, 5 days per week for 6 weeks, can restore the CAST-calpain-2 signaling pathway, alleviate Huntington’s disease-related neuropathological changes, improve motor function, and increase the survival rate of R6/2 mice by 30% at 12 weeks. At the same dosage and administration frequency but for 5 months, CAST-calpain-2 stabilizer-1 can also restore the same signaling pathway, reduce neuropathological changes and neuroinflammation associated with tauopathy, and enhance both short-term and long-term memory in PS19 mice.