AEP-IN-3

AEP-IN-3 is a potent orthosteric inhibitor of Asparagine endopeptidase (AEP). The primary reference describes the structure activity relationship and is disclosing orthogonal structural analogs from the same series or unrelated allosteric inhibitors like AEP-IN-2. The available negative control is considered a valuable reference in cellular PD assays. The selectivity is demonstrated on a molecular panel of proteases, but what is missing is an MS based chemo proteomic characterization of cellular targets that are covalently engaged by AEP-IN-3. Although the co-crystal structure of AEP in complex with AEP-IN-3 is missing, a representative co-crystal structure of a close analog is provided. The in vivo experiments are limited to a single endpoint measurement of AEP activity and TAU modulation after 5 days, without any dose dependency, exposure data, a timely resolved PK/PD profile or control compounds.

This concentration seems a little high for a ~ 200 nM covalent inhibitor that hasn't been profiled in selectivity assays (e.g. by ABPP). Therefore up to 1 µM would be a safer concentration range.