Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders.
Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1's effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.
Beth Israel Deaconess Medical Center, Boston, MA, USA.|Boston Children's Hospital, Department of Cardiology, Boston, MA, USA.
Vassilios J
VJ
Bezzerides
Beth Israel Deaconess Medical Center, Boston, MA, USA.|Massachusetts General Hospital, Boston, MA, USA.
Aifeng
A
Zhang
Massachusetts General Hospital, Boston, MA, USA.
Ling
L
Xiao
Beth Israel Deaconess Medical Center, Boston, MA, USA.|Massachusetts General Hospital, Boston, MA, USA.
Bridget
B
Simonson
Beth Israel Deaconess Medical Center, Boston, MA, USA.|ChemBio Discovery Solutions, Lexington, MA, USA.
Santosh A
SA
Khedkar
Graduate School of Medicine Kyoto University, Kyoto City, Japan.
Shiro
S
Baba
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Filomena
F
Ottaviano
Warp Drive Bio Inc., Cambridge, MA, USA.
Stacey
S
Lynch
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Katherine
K
Hessler
Beth Israel Deaconess Medical Center, Boston, MA, USA.|Warp Drive Bio Inc., Cambridge, MA, USA.
Alan C
AC
Rigby
Massachusetts General Hospital, Boston, MA, USA.
David
D
Milan
Beth Israel Deaconess Medical Center, Boston, MA, USA. sdas@partners.org.|Massachusetts General Hospital, Boston, MA, USA. sdas@partners.org.
Saumya
S
Das
Beth Israel Deaconess Medical Center, Boston, MA, USA.|Massachusetts General Hospital, Boston, MA, USA.
Anthony
A
Rosenzweig
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases