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 B Gurley, Matthew A Sparks, Justin A MacDonald, Timothy A J Haystead

Cell Chem Biol. 2018 Oct 18;25(10):1195-1207.e32.

PMID: 30033129

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1030203816	HS38		1030203-81-6	Price

Catalog Number

Product Name

Structure

CAS Number

Price

AP1030203816

HS38

1030203-81-6

Price

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