Targeting Pim kinases and DAPK3 to control hypertension

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dc.contributor.authorCarlson, David A.
dc.contributor.authorSinger, Miriam R.
dc.contributor.authorSutherland, Cindy
dc.contributor.authorRedondo, Clara
dc.contributor.authorAlexander, Leila T.
dc.contributor.authorHughes, Philip Floyd
dc.contributor.authorKnapp, Stefan
dc.contributor.authorGurley, Susan B.
dc.contributor.authorSparks, Matthew A.
dc.contributor.authorMacDonald, Justin Anthony
dc.contributor.authorHaystead, Timothy Arthur James
dc.date.accessioned2019-04-24T15:01:53Z
dc.date.available2019-04-24T15:01:53Z
dc.date.issued2018-07-04
dc.description.abstractSustained 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.en_US
dc.description.grantingagencyCanadian Institutes of Health Research - Foundation Schemeen_US
dc.identifier.citationCarlson, 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. "Journal of Chemical Biology", 6, 1-57. http://dx.doi.org/10.1016/j.chembiol.2018.06.006en_US
dc.identifier.doihttp://dx.doi.org/10.1016/j.chembiol.2018.06.006en_US
dc.identifier.grantnumberMOP-97988; MOP-133543en_US
dc.identifier.urihttp://hdl.handle.net/1880/110192
dc.identifier.urihttps://doi.org/10.11575/PRISM/43849
dc.language.isoengen_US
dc.publisher.departmentBiochemistry & Molecular Biologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.publisher.institutionDuke University Medical Centeren_US
dc.publisher.institutionUniversity of Oxforden_US
dc.subjectDAPK3en_US
dc.subjectZIPKen_US
dc.subjecthypertensionen_US
dc.subjectvascular smooth muscleen_US
dc.subjectdeath-associated protein kinaseen_US
dc.subjectPim kinase, Pim-1, Pim-2, Pim-3en_US
dc.titleTargeting Pim kinases and DAPK3 to control hypertensionen_US
dc.typejournal articleen_US
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