Background:

EMD638683 is a highly selective inhibitor of the serum and glucocorticoid inducible kinase (SGK) with IC50 value of 3 μM [1].
SGK is a group of serine/threonine kinases that consists of SGK1, SGK2 and SGK3. Among these, SGK1 takes participate in the signaling pathway that regulates the sodium channel, cell proliferation, cell survival and many other cellular processes. The transcription of SGK1 can be up-regulated by the activation of serum, mineralocorticoids and glucocorticoids. SGK1 enhanced the renal tubular reabsorption of sodium after the high salt activation. Besides that, SGK is highly expressed in some sorts of tumors while down-regulated in some other tumors such as APC. The selective SGK1 inhibitor EMD638683 showed inhibition effects on all the three forms of SGK but not for other kinases. It can affect the phosphorylation of NDRG1in vitro and meanwhile exert anti-tumor or anti-hypertensive efficacy in vivo [1, 2].
In the biochemical kinase assays, EMD638683 at concentration of 1 μM inhibited 85%, 71% and 75% activities of SGK1, SGK2 and SGK3, respectively. It also had inhibitory effects on MSK1 (mitogen-and stress-activated protein kinase 1) and PRK2 (protein kinase C-related kinase 2) with IC50 values of ≤ 1 μM. For other 64 kinases, such as MAPK, PRAK and Syk, EMD638683 showed no significant inhibition. In HeLa cells, EMD638683 suppressed the phosphorylation of NDRG1, which is a target of SGK1, with IC50 value of 3.35 μM. Besides that, EMD638683 treated CaCo-2 cells displayed increased depolarized mitochondria and enhanced caspase activity after the exposure to radiation [1, 2].
In mice treated with the carcinogenic drugs, the administration of EMD638683 at dose of 600 mg/kg/day significantly lowered the colon weight and reduced the developing tumors. In another mice experiment, administration of EMD638683 increased the urinary output and normalized the systolic blood pressure in mice treated with 10% fructose drinking water. It indicated that EMD638683 might be an attracted drug for the hypertension treatment in diabetic patients [1, 2].
参考文献:
[1] Towhid S T, Liu G L, Ackermann T F, et al. Inhibition of colonic tumor growth by the selective SGK inhibitor EMD638683. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology, 2012, 32(4): 838-848.
[2] Ackermann T F, Boini K M, Beier N, et al. EMD638683, a novel SGK inhibitor with antihypertensive potency. Cellular Physiology and Biochemistry, 2011, 28(1): 137-146.