Tauopathies are neurodegenerative diseases characterized by the formation of tau protein neurofibrillary tangles in the brain. Tau is a substrate of the protease caspase-6, which has been found to be associated with tau tangles in post-mortem brain tissue of people with Alzheimer’s disease. Caspase-6 inhibition may suppress Alzheimer’s disease progression, but selective inhibitors of caspase-6 have not yet been identified. Utilizing a small molecule-cysteine disulfide trapping (tethering) technology, we have discovered specific inhibitors of caspase-6 by targeting a non-active-site cysteine unique to caspase-6. Optimization of the identified electrophile and linker has led to our development of selective, covalent small molecule inhibitors of caspase-6 with more than 10,000-fold greater potency over caspases -2, -3, and -7. Further crystallographic analysis has revealed that inhibition occurs through partial occupation of the substrate binding groove and locking of caspase-6 in a nonfunctional active conformation.

Development of covalent caspase-6 inhibitors derived from disulfide trapping (tethering)

253rd National Meeting (2017)

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