Description:
Project IDs: D2015-09 and D2016-81
Background:
Autophagy is a self-degradation process of cellular organelles that helps defend against metabolic stress, maintain metabolic equilibrium, arbitrate cell fate decisions, and safeguard genomic stability. Deficient autophagy has been associated with over 100 diseases, and experimental enhancement of autophagy often extenuates disease severity in nonhuman models, ranging from cancers to muscular dystrophies to amyotrophic lateral sclerosis. Despite autophagy’s involvement in these diseases, it is a complicated process involving over 60 proteins and is not well understood. Currently, autophagy is manipulated by starvation or with rapamycin derivative. Though, these approaches have proven invaluable in managing transplant rejection, hyperplastic diseases and cancers, but they carry substantial chronic toxicity and have low brain penetrance. Recently, Lanthionine ketimine (LK) and its brain penetrable ethyl ester (LKE) have been shown to activate autophagy process in vivo and in vitro and improve disease states, including ALS, Alzheimer’s, and stroke. Although it has therapeutic properties, LKE lacks potency and stability. Therefore, there still exists a need for therapeutic to treat neurological disorders.
Invention Description:
Researchers at the University of Toledo have developed a novel class of Lanthionine ketimine derivatives that are potently neuroprotective and stimulates cell autophagy. By incorporating phosphonates, LKE derivatives were shown to be more stable and less prone to decomposition. The novel compound is better at handling diseases such as neoplastic and central nervous system pathologies caused by autophagy impairment.
Applications:
Neurodegenerative disease such as ALS, Alzheimer, Parkinson’s.
Advantages:
• Greater stability due to incorporation of phosphates relative to carboxylates.
• Better bioavailability and cellular permeability.
• Better potency due to increased charged density.
• Improved efficacy that the current derivatives.
IP Status: Patent Pending - WO2017147440 A1
Publications:
Shen D, Hensley K, Denton T. Multiple-step, one-pot synthesis of 2-substituted-3-phosphono-1-thia-4-aza-2-cyclohexene-5-carboxylates and their corresponding ethyl esters. BioOrg & Med Chem Letters. 2018; 28(4) p562-565.
Hensley K et al. Autophagy Modulation by Lanthionine Ketimine Ethyl Ester Improves Long-Term Outcome after Central Fluid Percussion Injury in the Mouse. J Neurotrauma. 2016 Aug 15;33(16):1501-13.
Hensley, et al. A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies. Neurobiol Dis. 2015 Dec; 84:60-8