KN-93 Phosphate

KN-93 phosphate is the water soluble form of KN-93. It is a potent, selective and cell permeable inhibitor of CaM kinase II (IC50= 0.37 μm, Ki=370 nm) [1]
CaMK II (calcium/calmodulin-dependent protein kinase II) is a multifunctional serine/threonine kinase with various roles in different physiological systems.
Since CaMK II can enhance cell proliferation, the CaMK II inhibitor KN-93 blocked the cell proliferation by regulating the expression of p53 and p21 in human hepatic stellate cells. [2] KN-93 inhibited the autophosphorylation of both α and β subunits of CaMK II. Moreover, KN-93 reduced dopamine level via modulating the TH reaction rate to reduce the Ca2+-mediated phosphorylation levels of the TH molecule in PC12h cells.[1] As CaMK II is necessary for cell cycle progression through G1, KN-93 also induced G1 cell cycle arrest and apoptosis in NIH 3T3 cells.[3]
In MRL/lpr Foxp3-GFP mice, KN-93 promoted the generation of Foxp3 regulatory T cells through the inhibition of CaMK IV in the spleen, peripheral lymph nodes and peripheral blood with decreased skin and kidney damage. [4] In a rat model of Parkinson's disease, intrastriatal injection of KN-93 relieved the levodopa-induced dyskinesia by suppressing the CaMK II activation. [5]
References:
[1] Sumi M, Kiuchi K, Ishikawa T, Ishii A, Hagiwara M, Nagatsu T, Hidaka H. The newly synthesized selective Ca2+/calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells. Biochem Biophys Res Commun. 1991 Dec 31;181(3):968-75.
[2] An P, Zhu JY, Yang Y, Lv P, Tian YH, Chen MK, Luo HS. KN-93, a specific inhibitor of CaMKII inhibits human hepatic stellate cell proliferation in vitro. World J Gastroenterol. 2007 Mar 7;13(9):1445-8.
[3] Tombes RM, Grant S, Westin EH, Krystal G. G1 cell cycle arrest and apoptosis are induced in NIH 3T3 cells by KN-93, an inhibitor of CaMK-II (the multifunctional Ca2+/CaM kinase). Cell Growth Differ. 1995 Sep;6(9):1063-70.
[4] Koga T, Mizui M, Yoshida N, Otomo K, Lieberman LA, Crispín JC, Tsokos GC.KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3⁺ regulatory T cells in MRL/lpr mice. Autoimmunity. 2014 Nov;47(7):445-50.
[5] Yang X, Wu N, Song L, Liu Z. Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson's disease. Neuropsychiatr Dis Treat. 2013;9:1213-20. doi: 10.2147/NDT.S45422.

KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N -methylbenzylamine), a calcium/calmodulin-dependent protein kinase II inhibitor, is a direct extracellular blocker of voltage-gated potassium channels.[Pubmed:16368898]

J Pharmacol Exp Ther. 2006 Apr;317(1):292-9.

The effect of Ca(2+)/calmodulin-dependent protein kinase II (CaMK II) on voltage-gated ion channels is widely studied through the use of specific CaMK II blockers such as 2-[N-(2-hydroxyethyl)]-N-(4methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-m ethylbenzylamine (KN-93). The present study demonstrates that KN-93 is a direct extracellular blocker of a wide range of cloned Kv channels from a number of different subfamilies. In all channels tested, the effect of 1 microM KN-93 was independent of CaMK II because 1 microM2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylam ine, phosphate (KN-92), an inactive analog of KN-93, caused similar inhibition of currents. In addition, dialysis of cells with 10 microM CaMK II inhibitory peptide fragment 281-301 (CIP) had no effect on current kinetics and did not prevent the inhibitory effect of KN-93. The IC(50) for block of the Kv1.5 channel (used as an example to determine the nature of KN-93 block) was 307 +/- 12 nM. KN-93 blocked open channels with little voltage dependence that did not alter the V(1/2) of channel activation. Removal of P/C-type inactivation by mutation of arginine 487 to valine in the outer pore region of Kv1.5 (R487V) greatly reduced KN-93 block, whereas enhancement of inactivation induced by mutation of threonine 462 to cysteine (T462C) increased the potency of KN-93 by 4-fold. This suggested that KN-93 acted through promotion and stabilization of C-type inactivation. Importantly, KN-93 was ineffective as a blocker when applied intracellularly, suggesting that CaMK II-independent effects of KN-93 on Kv channels can be circumvented by intracellular application of KN-93.

KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart.[Pubmed:9864285]

J Pharmacol Exp Ther. 1998 Dec;287(3):996-1006.

The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase) mediates Ca++-induced augmentation of L-type Ca++ current (ICa); therefore it may act as a proarrhythmic signaling molecule during early afterdepolarizations (EADs) due to ICa. To investigate the hypothesis that ICa-dependent EADs are favored by CaM kinase activation EADs were induced with clofilium in isolated rabbit hearts. All EADs were rapidly terminated with ICa antagonists. Hearts were pretreated with the CaM kinase inhibitor KN-93 or the inactive analog KN-92 (0.5 microM) for 10 min before clofilium exposure. EADs were significantly suppressed by KN-93 (EADs present in 4/10 hearts) compared to KN-92 (EADs present in 10/11 hearts) (P =.024). There were no significant differences in parameters favoring EADs such as monophasic action potential duration or heart rate in KN-93- or KN-92-treated hearts. CaM kinase activity in situ increased 37% in hearts with EADs compared to hearts without EADs (P =.015). This increase in CaM kinase activity was prevented by pretreatment with KN-93. In vitro, KN-93 potently inhibited rabbit myocardial CaM kinase activity (calculated Ki 100 microM). The actions of KN-93 and KN-92 on ICa and other repolarizing K+ currents did not explain preferential EAD suppression by KN-93. These data show a novel association between CaM kinase activation and EADs and are consistent with the hypothesis that the ICa and CaM kinase activation both contribute to EADs in this model.

The newly synthesized selective Ca2+/calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells.[Pubmed:1662507]

Biochem Biophys Res Commun. 1991 Dec 31;181(3):968-75.

We reported that one of the isoquinolinesulfonamide derivatives, KN-62, is a potent and specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) (Tokumitsu, H., Chijiwa, T., Hagiwara, M., Mizutani, A., Terasawa, M. and Hidaka, H. (1990) J. Biol. Chem. 265, 4315-4320). We have now investigated the inhibitory property of a newly synthesized methoxybenzenesulfonamide, KN-93, on CaMKII activity in situ and in vitro. KN-93 elicited potent inhibitory effects on CaMKII phosphorylating activity with an inhibition constant of 0.37 microM but this compound had no significant effects on the catalytic activity of cAMP-dependent protein kinase, Ca2+/phospholipid dependent protein kinase, myosin light chain kinase and Ca(2+)-phosphodiesterase. KN-93 also inhibited the autophosphorylation of both the alpha- and beta-subunits of CaMKII. Kinetic analysis indicated that KN-93 inhibits CaMKII, in a competitive fashion against calmodulin. To evaluate the regulatory role of CaMKII on catecholamine metabolism, we examined the effect of KN-93 on dopamine (DA) levels in PC12h cells. The DA levels decreased in the presence of KN-93. Further, the tyrosine hydroxylase (TH) phosphorylation induced by KCl or acetylcholine was significantly suppressed by KN-93 in PC12h cells while events induced by forskolin or 8-Br-cAMP were not affected. These results suggest that KN-93 inhibits DA formation by modulating the reaction rate of TH to reduce the Ca(2+)-mediated phosphorylation levels of the TH molecule.

KN-93 Phosphate is a potent and specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with Ki of 0.37 μM, no remarkable inhibitory effects on APK, PKC, MLCK or Ca2+-PDE activities.

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