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.

DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

“…This likely provides a mechanism for the enhanced selectivity of most CLK1/2/4 inhibitors over closely-related CLK3. It is interesting to note that the most selective inhibitors including the casein kinase 2 alpha 1 (CK2α1) inhibitor GO289 47 , the dual PIM/DAPK3 inhibitor HS56 48 , the selective DAPK3 inhibitor HS94 and HS184 48 and the CLK inhibitor MU1210 27 do not significantly interact with the hinge back bone, but rather engage contacts at the back pocket particularly with the DFG-1 residue. Such binding modes have also been noted by the KLIFS database 49 .…”

RSK2 contributes to myogenic vasoconstriction of resistance arteries by activating smooth muscle myosin and the Na + /H + exchanger

“…They include the zipper-interacting kinase (DAPK3) (7), integrin-linked kinase (ILK) (8), IκBK (inhibitor κB kinase 2) (9), and Pim kinase (10). A newly developed dual Pim/DAPK3 inhibitor reduces caudal artery contractility and decreases blood pressure in spontaneously hypertensive mice (10). These kinases phosphorylate RLC 20 , leading to smooth muscle contraction, but their specific physiological roles in the myogenic response have not been studied.…”

Novel Functions of Death-Associated Protein Kinases through Mitogen-Activated Protein Kinase-Related Signals

“…Recently, a dual Pim/DAPK3 inhibitor (HS56) was synthesized using crystal structure-guided medicinal chemistry techniques [ 108 ]. HS56 reduced Pim kinase-induced myosin phosphorylation and the contractility of vascular smooth muscle in spontaneously hypertensive RenTG mice, suggesting a novel multi-target strategy for hypertensive diseases [ 108 ]. In the same report, selective DAPK3 inhibitors (HS94 and HS148) were also developed [ 108 ].…”