A novel small molecule tyrosine kinase inhibitor (GUtinib) preferentially targets discoidin domain receptors and reduces toxic proteins in neurodegeneration (5398)

Objective: 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). Background: 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). Design/Methods: We evaluated several animal models of neurodegeneration for human alpha-Synuclein, amyloid-beta and hyper-phosphorylated tau. Results: 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. Conclusions: 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. Disclosure: Dr. Fowler has nothing to disclose. Dr. Hebron has nothing to disclose. Dr. Torres-Yaghi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie.Dr. Pagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sunovion, Teva, Acadia, Adamas, AbbVie, Medtronic, USWorldMeds, Merz.Dr. Ahn has nothing to disclose. Dr. Moussa has nothing to disclose.