Nitrile warhead and new P5 scaffolds yield a selective, brain-penetrant caspase-2 inhibitor for tau-related dementia research
- A broad SAR campaign on covalent-reversible peptidomimetics mapped the S2-S3 region of the caspase-2 binding site and identified 2-methylindoline-2-carboxylic acid and quinaldic acid as stable P5 groups.
- Swapping the aldehyde warhead for a nitrile in one step sharpened selectivity over other caspases while keeping potency, giving MUR-2425.
- MUR-2425 blocked formation of the neurotoxic Δtau314 fragment in vitro, showed stable ADMET behavior across species, reached the brain in mice, and bound covalently in a co-crystal structure.
💡 Points Based on the abstract
Nitrile for aldehyde is the right call: aldehydes are metabolically and chemically fragile, and reversible covalent nitriles usually keep potency with cleaner caspase selectivity. But the peptidomimetic backbone still worries me for brain exposure. I'd want brain-to-plasma unbound ratios, efflux data, and a kinact/KI readout against caspase-3/7 before calling it a tool compound.