Targeting Pim Kinases and DAPK3 to Control Hypertension

David A. Carlson, Miriam R. Singer, Cindy Sutherland, Clara Redondo, Leila T. Alexander, Philip F. Hughes, Stefan Knapp, Susan Gurley, Matthew A. Sparks, Justin A. MacDonald, Timothy A.J. Haystead

Research output: Contribution to journalArticle

3 Scopus citations

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. Carlson et al. use crystal structure-guided medicinal chemistry techniques to develop a dual Pim/DAPK3 inhibitor (HS56) that reduces myosin phosphorylation and contractility in smooth muscle. Their findings reveal the contribution of Pim kinases to the pathology of hypertension, suggesting a novel multi-target engagement strategy for molecularly targeted antihypertensive medications.

Original languageEnglish (US)
Pages (from-to)1195-1207.e32
JournalCell Chemical Biology
Volume25
Issue number10
DOIs
StatePublished - Oct 18 2018
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Carlson, D. A., Singer, M. R., Sutherland, C., Redondo, C., Alexander, L. T., Hughes, P. F., Knapp, S., Gurley, S., Sparks, M. A., MacDonald, J. A., & Haystead, T. A. J. (2018). Targeting Pim Kinases and DAPK3 to Control Hypertension. Cell Chemical Biology, 25(10), 1195-1207.e32. https://doi.org/10.1016/j.chembiol.2018.06.006