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Abstract Details

A novel small molecule tyrosine kinase inhibitor (GUtinib) preferentially targets discoidin domain receptors and reduces toxic proteins in neurodegeneration
Aging, Dementia, and Behavioral Neurology
P4 - Poster Session 4 (5:30 PM-6:30 PM)
10-007
Our laboratory demonstrated that multi-kinase inhibitors like nilotinib and bosutinib are optimal agents since they target both Abl and Discoidin Domain Receptors (DDR1/2) and Abl and SRC tyrosine kinases, respectively. These two agents are currently in phase II in DLB (nilotinib and bosutinib), PD and AD (nilotinib).
Tyrosine kinase inhibition (TKi) is a potential new strategy to target misfolded protein degradation in neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Lewy Body Dementia (DLB).
We evaluated several animal models of neurodegeneration for human alpha-Synuclein, amyloid-beta and hyper-phosphorylated tau.
Profiling the tyrosine kinase targets of several FDA-approved drugs shows that agents with high potency to Abl alone are ineffective and cannot clear toxic proteins, but a multikinase inhibition like Abl/SRC and DDRs is optimal for misfolded protein clearance. Here we report a novel tyrosine kinase inhibitor (GUtinib) that has the highest specificity to DDR1/2 and exhibits a high efficacy to clear human alpha-Synuclein, amyloid-beta and hyper-phosphorylated tau in several animal models of neurodegeneration.
Our data indicate that GUtinib preferentially targets DDR1 and 2, but not Abl, and induces autophagy at very low concentrations and higher efficacy than other multikinase inhibitors. Further toxicology experiments will be conducted to obtain pre-investigational new drug (pre-IND) status, and if the safety of GUtinib is acceptable this agent will be tested in first-in-human early development clinical trials.
Authors/Disclosures
Alan Fowler
PRESENTER 		Mr. Fowler has nothing to disclose.
No disclosure on file
Yasar A. Torres-Yaghi, MD Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Torres-Yaghi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amneal. Dr. Torres-Yaghi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Abbott. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Kyowa Kirin. Dr. Torres-Yaghi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Teva. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sunovion .
Fernando L. Pagan, MD, FÂ鶹´«Ã½Ó³»­ (Georgetown University Hospital Dept of Neurology) Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Acorda. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Adamas. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amneal. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merz. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Kyowa Kirin. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sunovion. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for US World Meds. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Supernus. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Adamas. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amneal. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurocrine. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Supernus. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Clinical Parkinsonism and related Disorders. Dr. Pagan has stock in Keiferx. The institution of Dr. Pagan has received research support from US World Meds. The institution of Dr. Pagan has received research support from Novartis.
No disclosure on file
Charbel E. Moussa, PhD, MB (Georgetown University) Dr. Moussa has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for KeifeRX LLC. Dr. Moussa has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sun Pharmaceuticals Research Industry. Dr. Moussa has received stock or an ownership interest from Orphan Therapeutics. The institution of Dr. Moussa has received research support from NIA. The institution of Dr. Moussa has received research support from Sun Pharmaceuticals Research Industry. The institution of Dr. Moussa has received research support from Alzheimer's Association . Dr. Moussa has received intellectual property interests from a discovery or technology relating to health care. Dr. Moussa has received intellectual property interests from a discovery or technology relating to health care. Dr. Moussa has received publishing royalties from a publication relating to health care. Dr. Moussa has received personal compensation in the range of $500-$4,999 for serving as a Grant reviewer with DG Information Technology. Dr. Moussa has received personal compensation in the range of $0-$499 for serving as a Peer Reviews with National Institutes of Health.