KN-93 is a CaMKII (Calcium/calmodulin-dependent protein kinase II) blocker. It elicited potent inhibitory effects on CaMKII phosphorylating activity with an inhibition constant of 0.37μM but had no significant effects on the catalytic activity of CAMP-dependent protein kinase, Ca2+/phospholipid dependent protein kinase, myosin light chain kinase and Ca2+-phosphodiesterase. KN-93 also inhibited the autophosphorylation of both the α- and β-subunits of CaMKII. KN-93 inhibited dopamine formation by modulating the reaction rate of TH to reduce the Ca2+-mediated phosphorylation levels of the tyrosine hydroxylase molecule in PC12h cells[4]. KN-93 also works as a direct extracellular blocker of voltage-gated potassium channels with IC50 value of 307±12nM for block of the Kv1.5. KN-93 acted through promotion and stabilization of C-type inactivation. 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[5]. KN-93 inhibits IKr in mammalian cardiomyocytes[6].
作用机制
KN-93 inhibits CaMKII in a competitive fashion against calmodulin.[4]
KN-93 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse astrocytes
10 µM
15 min
Inhibition of CaMKII activity, reducing MLC1 protein dimerization
Cells. 2022 Aug 26;11(17):2656.
HEK293T cells
10 μM
4 h
To screen the upstream kinase for PRMT6
Mol Cell. 2021 Mar 18;81(6):1276-1291.e9.
U251 cells
10 µM
15 min
Inhibition of CaMKII activity, reducing MLC1 protein phosphorylation
Cells. 2022 Aug 26;11(17):2656.
BAP1-KO MeT-5A cells
7.5 µM
48 h
KN-93 significantly induced apoptosis in BAP1-KO cells by increasing intracellular Ca2+ concentration and inhibiting CAMK2D activity.
Cell Death Discov. 2023 Jul 21;9(1):257.
BAP1-KO HOMC-D4 cells
7.5 µM
48 h
KN-93 significantly induced apoptosis in BAP1-KO cells by increasing intracellular Ca2+ concentration and inhibiting CAMK2D activity.
Cell Death Discov. 2023 Jul 21;9(1):257.
Y-MESO-9 cells
7.5 µM
48 h
KN-93 significantly induced apoptosis in BAP1-KO cells by increasing intracellular Ca2+ concentration and inhibiting CAMK2D activity.
Cell Death Discov. 2023 Jul 21;9(1):257.
Human AC-16 cardiomyocytes
50 μM
1 h
Pre-treatment with KN-93 reduced doxorubicin-induced ROS generation and cell death in RGS11 knockout AC-16 cells.
Redox Biol. 2022 Nov;57:102487.
HEK293 cells
10 μM
14 h
To investigate the inhibitory effect of KN-93 on CaMKII, it was found that KN-93 aggravated the accumulation of ubiquitinated proteins.
EMBO Rep. 2024 Oct;25(10):4488-4514.
HeLa cells
10 μM
14 h
To investigate the inhibitory effect of KN-93 on CaMKII, it was found that KN-93 aggravated the accumulation of ubiquitinated proteins.
EMBO Rep. 2024 Oct;25(10):4488-4514.
NRVM (neonatal rat ventricular myocytes)
10 μM
24 h
KN-93 treatment significantly reduced the p-CaMKII levels in PRMT1-depleted cells, restored cell size, and attenuated the increase in ANP and β-MHC gene expression.
Nat Commun. 2018 Nov 30;9(1):5107.
KN-93 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
LPS-induced acute lung injury model
Intraperitoneal injection
10mg/kg
The first injection was performed 2h before LPS administration, followed by injections every 24h for 48h.
KN-93 suppressed the phosphorylation of CaMK4 and significantly inhibited NLRP3 inflammasome activation, leading to reduced IL-1β and IL-18 production, and ameliorated LPS-induced acute lung injury.
Front Immunol. 2022 Jun 6;13:890710
SCID mice
BAP1-KO Y-MESO-9 xenograft model
Intraperitoneal injection
15 mg/kg
Administered on days 0, 4, 8,13, and 16, lasting 16 days
KN-93 significantly suppressed tumor growth of BAP1-KO Y-MESO-9 cells without causing weight loss and inhibited tumor growth by promoting apoptosis.
Cell Death Discov. 2023 Jul 21;9(1):257.
Mice
Diabetic myocardial ischemia model
Direct injection into the left ventricle
300 μg/kg
Single dose 10 minutes before surgery
KN-93 significantly increased the concentration levels of circulating myocardial enzymes and infarct size in DM hearts, decreased the release of CGRP, attenuated the recovery of cardiac function, and increased the interstitial fibrosis area, indicating that CaMKII plays an important role in PF-mediated cardioprotection.
Cell Biosci. 2016 Jun 1;6:37
Mice
Isoflurane anesthesia model
Intracerebroventricular injection
1 mM
Single injection, lasting 7 days
KN93 significantly diminished the protective effect of GLYX-13 on cognitive function and NR2B, CaMKII, and CREB levels, indicating that GLYX-13 ameliorates isoflurane-induced cognitive dysfunction via the NR2B/CaMKII/CREB signaling pathway.
Neural Regen Res. 2020 Jan;15(1):128-135
Mice
Chronic doxorubicin-induced cardiotoxicity model
Intraperitoneal injection
8 mg/kg
Every 4 days, total of 2 doses
KN-93 treatment significantly alleviated cardiac fibrosis in RGS11 knockdown mice.
Redox Biol. 2022 Nov;57:102487.
Nude mice
MDA-MB-231 xenograft model
Intraperitoneal injection
10 mg/kg
Once every three days for 12 days
To investigate the anti-tumor efficacy of KN-93 in combination with proteasome inhibitors, it was found that the combination significantly enhanced anti-tumor activity.
EMBO Rep. 2024 Oct;25(10):4488-4514.
Mice
Cardiac-specific PRMT1 knockout mice
Intraperitoneal injection
10 μM/kg
Once daily for 8 days
KN-93 treatment improved cardiac function in PRMT1-deficient mice, reduced left ventricular dilation and fibrosis, and decreased the expression of ANP and BNP.
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