An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury.
Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development.
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D064550:Death-Associated Protein Kinases; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000517:prevention & control*; D051379:Mice; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D011724:Pyridazines; C062482:pyridazine; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases