Death-associated protein kinase as a potential therapeutic target.
Death associated protein kinase (DAPK) is a calmodulin (CaM)-regulated serine/threonine protein kinase implicated in diverse apoptosis pathways, including those involved in neuronal cell death and tumour suppression. The requirement of DAPK catalytic activity for its proposed cell functions and the validation of protein kinases as therapeutic targets demand that DAPK be examined as a potential therapeutic target in human disease. The relevant placement of DAPK activity in apoptosis pathways is at an early stage of investigation, making its study as a therapeutic target tenuous. However, the current body of knowledge raises the possibility of DAPK as a therapeutic target for diseases characterised by rapid neurodegeneration, such as stroke or traumatic brain injury. The unmet need in these diseases is for an acute treatment schedule that might reduce neuronal loss. Bioavailable inhibitors of DAPK catalytic activity that target the central nervous system have a potential to fill this need. The development of such DAPK inhibitors is now feasible based on the recent emergence of enabling technology and knowledge. These include a quantitative and selective enzyme assay, a high resolution structure of the active catalytic domain and discovery of cell-permeable, low molecular weight inhibitors of CaM kinases that cross the blood-brain barrier. DAPK as a potential therapeutic target for cancer is less attractive due to the incomplete state of knowledge about DAPK and inherent limitations in drug development for the discovery of specific activators of genes downregulated by promoter hypermethylation. This article provides a brief summary of relevant research and the rationale that is at the foundation of this opinion.
Schumacher
Andrew M
AM
Drug Discovery Programme, Department of Molecular Pharmacology and Biological Chemistry, 303 East Chicago Avenue, Ward 8-196, Chicago, IL 60611, USA.
Velentza
Anastasia V
AV
Watterson
D Martin
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D002491:Central Nervous System Agents / Q000494:pharmacology / Q000627:therapeutic use; D002518:Ceramides / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009410:Nerve Degeneration / Q000188:drug therapy; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000737:chemistry / Q000502:physiology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002147:Calmodulin; D002491:Central Nervous System Agents; D002518:Ceramides; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases