Caspase-2 as a target for the treatment of Alzheimer's disease and related dementias

Ort: Hörsaal der Pharmazeutischen Institute, Corrensstraße 48 in Münster

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Meeting ID: 620 7737 3956
Passcode: DPhG

Successful therapies for Alzheimer's disease and related dementias (ADRD) have remained frustratingly elusive. The tau mislocalization to dendritic spines causes synaptic dysfunction independently of neurodegeneration, while the formation of Δtau314, a 35-kDa tau cleavage product, reversibly impairs cognitive and synaptic function in animal and cellular models of tauopathies. Caspase-2 (Casp2) is responsible for the creation of Δtau314; therefore, blocking this truncation can be a highly promising therapeutic approach for AD and other tauopathies. In the search for new drugs to inhibit caspase-2, we have developed a series of > 150 peptide Casp-2 inhibitors, based on rational-design strategy approaches, to enlighten the mechanism by which Casp2 impacts synaptic function. The best compounds there of are highly active and selective Casp-2 inhibitors that block Δtau314 formation, prevented tau from accumulating in dendritic spines and preserved excitatory neurotransmission in cultured primary hippocampal neurons in a model of frontotemporal dementia. Furthermore, we are pursuing a fragment-based drug discovery approach for the development of more drug-like small molecules targeting caspase-2 to overcome hurdles for their application as CNS drugs. Our recent HTS study using a library of 1920 electrophilic fragments yields promising results with significant affinity and selectivity, providing an excellent starting point for further development of small molecule caspase-2 inhibitors.

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Mit freundlichen Grüßen
Anna Junker