An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury

Anastasia V. Velentza, Mark Wainwright, Magdalena Zasadzki, Salida Mirzoeva, Andrew M. Schumacher, Jacques Haiech, Pamela J Focia, Martin Egli, D Martin Watterson*

*Corresponding author for this work

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3465-3470
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume13
Issue number20
DOIs
StatePublished - Oct 20 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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