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Targeting Pim Kinases and DAPK3 to Control Hypertension.

Publication ,  Journal Article
Carlson, DA; Singer, MR; Sutherland, C; Redondo, C; Alexander, LT; Hughes, PF; Knapp, S; Gurley, SB; Sparks, MA; MacDonald, JA; Haystead, TAJ
Published in: Cell Chem Biol
October 18, 2018

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.

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Published In

Cell Chem Biol

DOI

EISSN

2451-9448

Publication Date

October 18, 2018

Volume

25

Issue

10

Start / End Page

1195 / 1207.e32

Location

United States

Related Subject Headings

  • Sequence Alignment
  • Rats, Sprague-Dawley
  • Proto-Oncogene Proteins c-pim-1
  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Muscle Contraction
  • Molecular Targeted Therapy
  • Models, Molecular
  • Mice
  • Male
 

Citation

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Carlson, D. A., Singer, M. R., Sutherland, C., Redondo, C., Alexander, L. T., Hughes, P. F., … Haystead, T. A. J. (2018). Targeting Pim Kinases and DAPK3 to Control Hypertension. Cell Chem Biol, 25(10), 1195-1207.e32. https://doi.org/10.1016/j.chembiol.2018.06.006
Carlson, David A., Miriam R. Singer, Cindy Sutherland, Clara Redondo, Leila T. Alexander, Philip F. Hughes, Stefan Knapp, et al. “Targeting Pim Kinases and DAPK3 to Control Hypertension.Cell Chem Biol 25, no. 10 (October 18, 2018): 1195-1207.e32. https://doi.org/10.1016/j.chembiol.2018.06.006.
Carlson DA, Singer MR, Sutherland C, Redondo C, Alexander LT, Hughes PF, et al. Targeting Pim Kinases and DAPK3 to Control Hypertension. Cell Chem Biol. 2018 Oct 18;25(10):1195-1207.e32.
Carlson, David A., et al. “Targeting Pim Kinases and DAPK3 to Control Hypertension.Cell Chem Biol, vol. 25, no. 10, Oct. 2018, pp. 1195-1207.e32. Pubmed, doi:10.1016/j.chembiol.2018.06.006.
Carlson DA, Singer MR, Sutherland C, Redondo C, Alexander LT, Hughes PF, Knapp S, Gurley SB, Sparks MA, MacDonald JA, Haystead TAJ. Targeting Pim Kinases and DAPK3 to Control Hypertension. Cell Chem Biol. 2018 Oct 18;25(10):1195-1207.e32.

Published In

Cell Chem Biol

DOI

EISSN

2451-9448

Publication Date

October 18, 2018

Volume

25

Issue

10

Start / End Page

1195 / 1207.e32

Location

United States

Related Subject Headings

  • Sequence Alignment
  • Rats, Sprague-Dawley
  • Proto-Oncogene Proteins c-pim-1
  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Muscle Contraction
  • Molecular Targeted Therapy
  • Models, Molecular
  • Mice
  • Male