@article{e403d87ae66a4a9d9d9aa82d265774bd,
title = "Targeting Pim Kinases and DAPK3 to Control Hypertension",
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.",
keywords = "DAPK3, Pim kinase, Pim-1, Pim-2, Pim-3, ZIPK, death associated protein kinase, hypertension, vascular smooth muscle contractility, zipper-interacting protein kinase",
author = "Carlson, {David A.} and Singer, {Miriam R.} and Cindy Sutherland and Clara Redondo and Alexander, {Leila T.} and Hughes, {Philip F.} and Stefan Knapp and Gurley, {Susan B.} and Sparks, {Matthew A.} and MacDonald, {Justin A.} and Haystead, {Timothy A.J.}",
note = "Funding Information: We wish to thank David M. Gooden with the Duke University Small Molecule Synthesis Facility for LC-MS support; Katherine Bendt and Robert C. Griffiths for performing all mouse acute infusion studies and data annotation; Ingo Korndoerfer and the team at CRELUX (Martinsried, Germany) for crystallography studies; Nathan Nicely at the Duke University Macromolecular X-ray Crystallography Shared Resource for crystallography expertise and PDB submission; Michael Walsh (University of Calgary) for helpful discussions regarding VSM data; Kavita Pillai, Juliane Totzke, and Kirsten Overdahl for helpful conversations. This work was supported in part by a grant from the Mandel foundation to T.A.J.H; the Canadian Institutes of Health Research (CIHR MOP-97988; CIHR MOP-133543) and the AIHS/Pfizer Translational Research Fund to J.A.M; the National Institute of Diabetes, Digestive and Kidney Diseases (Duke O'Brien Center for Kidney Research, NIH award number P30DK096493) to S.B.G.; and a grant from the Department of Veterans Affairs to MAS (#IK2BX002240). All animal experiments were conducted according to protocols approved by the institutional Animal Care and Use Committees for the University of Calgary, Duke University School of Medicine, and Durham VAMC. Funding Information: We wish to thank David M. Gooden with the Duke University Small Molecule Synthesis Facility for LC-MS support; Katherine Bendt and Robert C. Griffiths for performing all mouse acute infusion studies and data annotation; Ingo Korndoerfer and the team at CRELUX (Martinsried, Germany) for crystallography studies; Nathan Nicely at the Duke University Macromolecular X-ray Crystallography Shared Resource for crystallography expertise and PDB submission; Michael Walsh (University of Calgary) for helpful discussions regarding VSM data; Kavita Pillai, Juliane Totzke, and Kirsten Overdahl for helpful conversations. This work was supported in part by a grant from the Mandel foundation to T.A.J.H; the Canadian Institutes of Health Research (CIHR MOP-97988 ; CIHR MOP-133543 ) and the AIHS /Pfizer Translational Research Fund to J.A.M; the National Institute of Diabetes, Digestive and Kidney Diseases (Duke O'Brien Center for Kidney Research, NIH award number P30DK096493 ) to S.B.G.; and a grant from the Department of Veterans Affairs to MAS (# IK2BX002240 ). All animal experiments were conducted according to protocols approved by the institutional Animal Care and Use Committees for the University of Calgary, Duke University School of Medicine, and Durham VAMC. ",
year = "2018",
month = oct,
day = "18",
doi = "10.1016/j.chembiol.2018.06.006",
language = "English (US)",
volume = "25",
pages = "1195--1207.e32",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "10",
}