Lanthionine ketimine (LK) is an endogenous amino acid metabolite thought to form when promiscuous reactions of the transsulfuration pathway create thioether amino acid intermediates that undergo further transamination reactions catalyzed mostly by glutamine transaminase K (kynurenine aminotransferase). Cell penetrating ester derivatives of LKE have potent antioxidant, anti-neuroinflammatory and pro-neurotrophic abilities and reduce correlates of disease in diverse animal models of neurodegenerative pathologies. The precise mechanism of action for LK derivatives has remained elusive though LK-ethyl ester (LKE, also known as XN001) has proven to be a potent enhancer of cell autophagy in cell culture and in vivo. In the course of translational development of XN001 for neurodisease therapy, data was uncovered that this compound potently and selectively inhibits the cyclin dependent kinase-5(Cdk5)/p25 complex with no inhibition of Cdk5/p35. LKE /XN001 also inhibits Cdk5/p25 ability to phosphorylate its target S522 residue in CRMP2 (collapsin response mediator protein-2) in a cell-free system. Furthermore, LKE/XN001 reduces Cdk5-targeted CRMP2 phosphorylation and neurofilament phosphorylation in the Cln3Δex7/8mouse modeling Batten disease (juvenile neuronal ceroid lipofuscinosis) while simultaneously reducing p25 levels in the Cln3Δex7/8mouse cerebellum. Molecular modeling identified a candidate LKE/XN001 binding site on the interface between the Cdk5 activation loop and its p25 binding partner. The putative binding interaction involves a network of hydrogen bonding interactions and a key salt bridge between LKE/XN001 and R156 of Cdk5, which could conceivably encourage a less productive conformation of the holoenzyme. Antagonism of Cdk5/p25 signaling pathways could explain the broad neuro-therapeutic profile of LKE/XN001 and provides a biological rational for translational development of LK analogs for neuropathologies. Disclosure KH is inventor of XN001 and holds equity in XoNovo Ltd.