Multikinase Abl/DDR/Src Inhibition Produces Optimal Effects for Tyrosine Kinase Inhibition in Neurodegeneration.

ABSTRACT:

Background and objectives

Inhibition of Abelson (Abl) tyrosine kinase as a therapeutic target has been gaining attention in neurodegeneration. Post-mortem Alzheimer's and Parkinson's disease brains show that the levels of several other tyrosine kinases, including Discoidin Domain Receptors (DDR1/2) are elevated. Knockdown of these tyrosine kinases with shRNA reduces neurotoxic proteins, including alpha-synuclein, beta-amyloid and tau.

Methods

Direct profiling of the pharmacokinetics of multi-kinase inhibitors Nilotinib, Bosutinib, Bafetinib, Radotinib and LCB-03-0110 shows differential levels of brain penetration but the ability of these agents to reduce toxic proteins is independent of brain concentration and selectivity to Abl.

Results

Our results indicate that the

SUBMITTER: Fowler AJ 

PROVIDER: S-EPMC6544596 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature