CAST-calpain-2 stabilizer-1 is a blood-brain barrier permeable stabilizer of CAST-calpain-2 interaction. CAST-calpain-2 stabilizer-1 shows no activity against GSK3. CAST-calpain-2 stabilizer-1 can be used in the research of Huntington's disease and tauopathies [1].
In Vivo, CAST-calpain-2 stabilizer-1 (10 mg/kg; i.p.; 5 days per week; 6 weeks) restores CAST-calpain-2 signaling, reduces Huntington's disease-associated neuropathology, improves motor function, and increases survival by 30% at 12 weeks in R6/2 mice[1]. CAST-calpain-2 stabilizer-1 (10 mg/kg; i.p.; 5 days per week; 5 months) restores CAST-calpain-2 signaling, reduces tauopathy-associated neuropathology and neuroinflammation, and improves both short-term and long-term memory in PS19 mice[1].
In Vitro, CAST-calpain-2 stabilizer-1 (dose-response range) potently restores mitochondrial membrane potential in HdhQ111 mouse striatal neuron-like cells with an EC50 of ~2.77 μM[1]. CAST-calpain-2 stabilizer-1 (0-20 μM) upregulates CAST protein expression in HdhQ111 mouse striatal neuron-like cells with an EC50 of ~3.55 μM[1]. CAST-calpain-2 stabilizer-1 (0.625-10 μM) reduces mitochondrial ROS production in HdhQ111 mouse striatal neuron-like cells with an IC50 of ~1.43 μM[1]. CAST-calpain-2 stabilizer-1 enhances the endogenous interaction between CAST and calpain-2 in HdhQ111 mouse striatal neuron-like cells[1]. CAST-calpain-2 stabilizer-1 (0-500 μM; 40 min (with lysates); 5 min (Pronase digestion)) directly binds and stabilizes CAST protein in HdhQ111 mouse striatal neuron-like cell lysates in a dose-dependent manner[1]. CAST-calpain-2 stabilizer-1 (10 μM (TMRM assay); 5-10 μM (MTT assay); 48 h (TMRM assay)) requires endogenous CAST and calpain-2 to exert its mitochondrial protective and viability-enhancing effects in HdhQ111 mouse striatal neuron-like cells[1]. CAST-calpain-2 stabilizer-1 (1 μM; 5 consecutive days) restores neuronal marker expression, suppresses calpain-2 activity, and rescues neurite outgrowth in human patient iPSC-derived HD medium spiny neurons[1].
References:
[1]. Hu D, et al. A small-molecule stabilizer of the calpastatin-calpain-2 complex restores mitochondrial function and mitigates neurodegeneration. Sci Adv. 2026;12(13):eaeb1174.
In Vivo, CAST-calpain-2 stabilizer-1 (10 mg/kg; i.p.; 5 days per week; 6 weeks) restores CAST-calpain-2 signaling, reduces Huntington's disease-associated neuropathology, improves motor function, and increases survival by 30% at 12 weeks in R6/2 mice[1]. CAST-calpain-2 stabilizer-1 (10 mg/kg; i.p.; 5 days per week; 5 months) restores CAST-calpain-2 signaling, reduces tauopathy-associated neuropathology and neuroinflammation, and improves both short-term and long-term memory in PS19 mice[1].
In Vitro, CAST-calpain-2 stabilizer-1 (dose-response range) potently restores mitochondrial membrane potential in HdhQ111 mouse striatal neuron-like cells with an EC50 of ~2.77 μM[1]. CAST-calpain-2 stabilizer-1 (0-20 μM) upregulates CAST protein expression in HdhQ111 mouse striatal neuron-like cells with an EC50 of ~3.55 μM[1]. CAST-calpain-2 stabilizer-1 (0.625-10 μM) reduces mitochondrial ROS production in HdhQ111 mouse striatal neuron-like cells with an IC50 of ~1.43 μM[1]. CAST-calpain-2 stabilizer-1 enhances the endogenous interaction between CAST and calpain-2 in HdhQ111 mouse striatal neuron-like cells[1]. CAST-calpain-2 stabilizer-1 (0-500 μM; 40 min (with lysates); 5 min (Pronase digestion)) directly binds and stabilizes CAST protein in HdhQ111 mouse striatal neuron-like cell lysates in a dose-dependent manner[1]. CAST-calpain-2 stabilizer-1 (10 μM (TMRM assay); 5-10 μM (MTT assay); 48 h (TMRM assay)) requires endogenous CAST and calpain-2 to exert its mitochondrial protective and viability-enhancing effects in HdhQ111 mouse striatal neuron-like cells[1]. CAST-calpain-2 stabilizer-1 (1 μM; 5 consecutive days) restores neuronal marker expression, suppresses calpain-2 activity, and rescues neurite outgrowth in human patient iPSC-derived HD medium spiny neurons[1].
References:
[1]. Hu D, et al. A small-molecule stabilizer of the calpastatin-calpain-2 complex restores mitochondrial function and mitigates neurodegeneration. Sci Adv. 2026;12(13):eaeb1174.