Neuropore scientists presented autophagy program data at the 2013 AD/PD meeting March 4th -10th, in Florence, Italy.
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*Published abstract #A-459-0013-01569, 2013 AD/PD meeting in Florence, Italy.
Development of a novel series of PI3K modulators designed to promote autophagy and the cellular clearance of neurotoxic peptides
Wolf Wrasidlo1,2, Igor Tsigelny2, Diana L. Price1, Douglas W. Bonhaus1, Amy D. Paulino1, Herbert Moessler1,3, Edward Rockenstein2, Eliezer Masliah2
1Neuropore Therapies, Inc., San Diego, CA 92121.
2University of California, San Diego, Department of Neuroscience and the Alzheimer’s Disease Research Center (ADRC), La Jolla, CA 92093.
3EVER Neuropharma, Unterach, AUSTRIA
Background: Dysregulation of autophagy and consequent cellular accumulation of aberrant toxic protein aggregates may be the common underlying basis of many neurodegenerative disorders. Autophagy can be modulated via the AKT-mTOR pathway and pharmacological inhibitors of this pathway, such as rapamycin acting at mTOR, activate autophagy and to have beneficial effects in animal models of neurodegenerative disorders.
Objectives: Since PI3K regulates the AKT-mTOR pathway we tested whether a novel series of PI3K modulators could affect the AKT-mTOR pathway, increase autophagy and promote the clearance of aberrant neurotoxic proteins.
Methods: Structure-based design was used to generate a series of structurally novel ligands aimed to interact with a selected region of the catalytic domain of PI3K. In vitro and in vivo studies were then conducted to characterize the effects of these molecules on the AKT-mTOR pathway, cellular markers of autophagy and the clearance of amyloid-beta and alpha-synuclein.
Results: NPT-520-34 inhibited the PI3K-AKT-mTor pathway, promoted autophagy, and reduced Abeta1-42 oligomers or alpha-synuclein accumulation in vitro. NPT-520-34 has favorable ADME properties, good oral bioavailability (29%), and no identified safety issues. In vivo studies confirmed biological activity, promotion of autophagy, and clearance of neurotoxic peptide oligomers.
Conclusions: A novel PI3K modulator, NPT-520-34, reduced alpha-synuclein accumulation and toxicity both in vitro and in vivo by increasing autophagy mediated clearance of oligomers. Studies are underway to assess the utility of NPT-520-34 as a potential therapeutic for the treatment of a wide range of neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple systems atrophy and dementia with Lewy bodies.