Why SGK1 May Be the Key to Unlocking Advanced LQTS Treatments
We are now Thryv.
LQT Therapeutics Inc. has changed its name to Thryv Therapeutics Inc.
SGK1 (Serum/Glucocorticoid Regulated Kinase 1) is a serine/threonine protein kinase that plays an important role in cellular stress response. This kinase activates certain sodium, potassium and chloride channels, suggesting an involvement in the regulation of processes such as cell survival and neuronal excitability.
Laboratory science has long shown that SGK1’s cellular stress response contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake. However, fairly recently, SGK1 has been further studied related to its effect on cardiac repolarization.
Simply, as SGK1 is involved in regulation of sodium channel in cardiac cells, any over-activity of this kinase function recapitulates Long QT Syndrome and is associated with heart arrhythmias.
Prior research with transgenic mice has shown that mice expressing constitutively active SGK1, resulting in increases in the late Na+ current, are prone to arrhythmias, while mice expressing dominant negative SGK1 are protected from arrhythmias. It’s precisely that data set that suggests SGK1 is a prime target for shortening action potential duration (APD) in Long QT Syndrome Types 1, 2, and 3, which covers approximately 90 percent of all LQT Syndrome genotypes.
SGK1’s neuronal excitability and its effect in action potential morphology (APM) of cardiomyocytes has captured the full attention of LQT Therapeutics’ laboratory scientists.
At LQT Therapeutics, our team is aiming to develop a potent SGK1 inhibitor. We have a group of highly-qualified chemists who synthesize new molecules, turning their work, in turn, over to an equally competent team of biologists who then study the biological effects of these molecules.
The potency of the synthesized SGK1 inhibitor molecules are tested by both biochemical kinase assays and whole-cell kinase assays. The team then studies the potency of these molecules to decrease the action potential duration of Long QT Syndrome patient-derived cardiomyocytes. Following in vitro testing, the team then focuses on the effectiveness of its molecule in rodent models of Long QT Syndrome.
In addition to investigating the effectiveness of our molecules in combating Long QT Syndrome, the research team also investigates whether these molecules are safe to be administered as drugs. To guarantee its limited off-target effects, the laboratory researchers investigate its toxicity, mutagenic potential and its effect on specific cardiac ion-channels, other receptors, other ion-channels in the body, and kinases. Finally, the LQT Therapeutics team identifies the best mode to administer the molecule in humans, which is gained by performing studies that investigate its permeability, stability in liver microsomes, oral/IV pharmacokinetic studies and formulation studies.
At present, LQT Therapeutics researchers have synthesized numerous molecules that have shown strong SGK1 inhibition potential. As experiments investigating their specificities have suggested they have low toxic and off-target effects, the team has also established a system to study the new molecules’ effects in Long QT Syndrome patient-derived cardiomyocytes. Our researchers have also gained a significant understanding of the permeability and distribution of the molecules when administered in rodents and in the near future they will be testing the effectiveness of their molecules on Long QT Syndrome through in vitro and in vivo experiments. Upon successfully concluding those steps, the team will then move forward to investigational new drug (IND) studies.
