This recent research paper discusses the development of small molecule inhibitors targeting caspase-2 (Casp2), an enzyme implicated in Alzheimer’s disease.
Traditional peptidic inhibitors pose challenges for central nervous system (CNS) drug development due to their poor bioavailability. Another way to discover inhibitors for targets that have active site cysteines is to perform electrophilic fragment screening. This typically delivers compounds lower in molecular weight than peptidomimetics, which is expected to lead to greater entry into the brain. With this in mind, we conducted an electrophilic fragment screening using a library of 1920 reactive chloroacetamide compounds and identified 64 promising hits. Many of these hits showed effective inhibition of Casp2, with some exhibiting significant selectivity over caspase-3 (Casp3). Further analysis confirmed the covalent binding of these fragments to the active site of Casp2, establishing a solid foundation for developing selective small-molecule inhibitors. The study highlights the potential of these compounds to address synaptic dysfunction in Alzheimer’s disease and related dementias, paving the way for future therapeutic developments.
