IngentaConnect Kinase Inhibitors as Potential Therapeutics for Acute and Chronic...

Abstract:

Kinases, which number > 500 in humans, are a class of enzymes that participate in an array of important functions within normal cellular physiology and during various pathological conditions. Due to the key role of kinases in the regulation of all aspects of cellular signaling and the well established contribution of kinase dysregulation to the etiology of many human pathologies, the development of kinase inhibitors has emerged as a therapeutic strategy for the treatment of human disease, including most notably oncology. Difficulties generating selective inhibitors have hampered their use in other therapeutic areas with less tolerance for off-target effects. However, with an increasing understanding of kinase structures and with the advent of newer inhibitor design strategies more highly selective inhibitors are beginning to emerge. This has prompted interest in utilizing kinase inhibitors in therapeutic areas beyond oncology, including acute and chronic neurodegenerative conditions for which disease modify therapies are lacking. This review provides a background in acute (i.e. brain ischemia and traumatic brain injury) and chronic (i.e. Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis) neurodegenerative conditions. Then, the role of several kinase (i.e. JNK3, p38 MAPK, ERK, PKCδ, ROCKII, GSK3, Cdk5, MLK, EphB3 kinase, RIP1 kinase, LRRK2, TTBK1, ASK1, CK, DAPK, and PKN1) that could serve as potential therapeutic targets for these maladies are reviewed.

Keywords: Kinase; inhibitor; phosphorylation; neurodegeneration; selectivity

Document Type: Research article

DOI: 10.2174/138161209789649330

Affiliations: 1: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139.

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Kinase Inhibitors as Potential Therapeutics for Acute and Chronic Neurodegenerative Conditions