2. Academic Validation
  3. Targeting Pim Kinases and DAPK3 to Control Hypertension

Targeting Pim Kinases and DAPK3 to Control Hypertension

  • Cell Chem Biol. 2018 Oct 18;25(10):1195-1207.e32. doi: 10.1016/j.chembiol.2018.06.006.
David A Carlson 1,  Miriam R Singer 1,  Cindy Sutherland 2,  Clara Redondo 3,  Leila T Alexander 3,  Philip F Hughes 1,  Stefan Knapp 4,  Susan B Gurley 5,  Matthew A Sparks 5,  Justin A MacDonald 2,  Timothy A J Haystead 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
  • 2 Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada.
  • 3 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • 4 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
  • 5 Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
  • 6 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: timothy.haystead@duke.edu.
PMID: 30033129 DOI: 10.1016/j.chembiol.2018.06.006
Abstract

Sustained vascular smooth muscle hypercontractility promotes hypertension and Cardiovascular Disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension. In vitro and ex vivo studies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility. In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications.

Keywords

DAPK3; Pim kinase; Pim-1; Pim-2; Pim-3; ZIPK; death associated protein kinase; hypertension; vascular smooth muscle contractility; zipper-interacting protein kinase.

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