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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1195-1207.e32 |
| Journal | Cell Chemical Biology |
| Volume | 25 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 18 2018 |
| Externally published | Yes |
Fingerprint
Keywords
- DAPK3
- death associated protein kinase
- hypertension
- Pim kinase
- Pim-1
- Pim-2
- Pim-3
- vascular smooth muscle contractility
- ZIPK
- zipper-interacting protein kinase
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Clinical Biochemistry
Cite this
Targeting Pim Kinases and DAPK3 to Control Hypertension. / Carlson, David A.; Singer, Miriam R.; Sutherland, Cindy; Redondo, Clara; Alexander, Leila T.; Hughes, Philip F.; Knapp, Stefan; Gurley, Susan; Sparks, Matthew A.; MacDonald, Justin A.; Haystead, Timothy A.J.
In: Cell Chemical Biology, Vol. 25, No. 10, 18.10.2018, p. 1195-1207.e32.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting Pim Kinases and DAPK3 to Control Hypertension
AU - Carlson, David A.
AU - Singer, Miriam R.
AU - Sutherland, Cindy
AU - Redondo, Clara
AU - Alexander, Leila T.
AU - Hughes, Philip F.
AU - Knapp, Stefan
AU - Gurley, Susan
AU - Sparks, Matthew A.
AU - MacDonald, Justin A.
AU - Haystead, Timothy A.J.
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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.
AB - 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.
KW - DAPK3
KW - death associated protein kinase
KW - hypertension
KW - Pim kinase
KW - Pim-1
KW - Pim-2
KW - Pim-3
KW - vascular smooth muscle contractility
KW - ZIPK
KW - zipper-interacting protein kinase
UR - http://www.scopus.com/inward/record.url?scp=85049324010&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049324010&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2018.06.006
DO - 10.1016/j.chembiol.2018.06.006
M3 - Article
C2 - 30033129
AN - SCOPUS:85049324010
VL - 25
SP - 1195-1207.e32
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 10
ER -