The p38alpha mitogen-activated protein kinase as a central nervous system drug discovery target.
Protein kinases are critical modulators of a variety of cellular signal transduction pathways, and abnormal phosphorylation events can be a cause or contributor to disease progression in a variety of disorders. This has led to the emergence of protein kinases as an important new class of drug targets for small molecule therapeutics. A serine/threonine protein kinase, p38alpha mitogen-activated protein kinase (MAPK), is an established therapeutic target for peripheral inflammatory disorders because of its critical role in regulation of proinflammatory cytokine production. There is increasing evidence that p38alpha MAPK is also an important regulator of proinflammatory cytokine levels in the central nervous system, raising the possibility that the kinase may be a drug discovery target for central nervous system disorders where cytokine overproduction contributes to disease progression. Development of bioavailable, central nervous system-penetrant p38alpha MAPK inhibitors provides the required foundation for drug discovery campaigns targeting p38alpha MAPK in neurodegenerative disorders.
Borders
Aaron S
AS
Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, IL 60611, USA. a-borders@northwestern.edu
de Almeida
Lucia
L
Van Eldik
Linda J
LJ
Watterson
D Martin
DM
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D048308:Mitogen-Activated Protein Kinase 14