Accession Number : AD1050403

Title :   Treating ALS by Targeting Pathological TDP-43

Descriptive Note : Technical Report,01 Sep 2016,31 Aug 2017

Corporate Author : Seattle Institute for Biomedical and Clinical Research Seattle United States

Personal Author(s) : Kraemer, Brian C

Full Text :

Report Date : 01 Sep 2017

Pagination or Media Count : 12

Abstract : TAR DNA-binding protein 43 kD (TDP-43) is the major aggregating disease protein in amyotrophic lateral sclerosis (ALS). Our previous work demonstrated pS409/410 TDP-43 mediates motor neuron toxicity of familial ALS-causing TDP-43 mutations, and identified two well conserved kinases, tau tubulin kinase 1 and tau tubulin kinase 2 (TTBK1/2). Kinases regulating TDP-43 phosphorylation present an attractive target for therapeutic intervention in ALS. Development of brain penetrant TTBK1 and TTBK2 inhibitors may provide a viable strategy for intervening in ALS. We have completed the primary screen of Specific Aim 1: Identification of TTBK1/2 selective kinase inhibitors. A collection of investigational kinase inhibitor drugs and CNS penetrant drugs (56,000 compounds in total) was screened to identify compounds quantitatively decreasing TTBK1 activity in vitro. Dose-validation analysis of hits is ongoing at Quellos High Throughput screening core. Subsequent follow-up analysis is simple model systems will be completed in the coming months.

Descriptors :   sclerosis , biomedical research , kinases , carrier proteins , dnabinding proteins , health care , inhibitors , therapy , metabolic diseases , neurodegenerative diseases , motor neurons , therapeutics , clinical trials

Subject Categories : Medicine and Medical Research

Distribution Statement : APPROVED FOR PUBLIC RELEASE