CaMKs are activated by the increase of intracellular calcium (Ca²⁺) and calmodulin concentrations. CaM is a Ca²⁺ effector protein, including two Ca²⁺ binding leaves connected by short junction region. Specifically, CaMKs are key regulators of calcium signaling in health and disease. CaMKII is one of the main effector enzymes relevant to calcium signal transduction in eukaryotic cells. Besides, CaMKII is a holoenzyme consisting of 12 56-60 kDa subunits. Moreover, CaMKII is a dodecamer oligomer of catalytic subunits, and each catalytic subunit can bind to a cam. The binding of cam to a single subunit activates its kinase activity, allowing the subunit to phosphorylate other proteins. Activation and autophosphorylation of CaMKII have been shown to be essential for inducing long-term potentiation. Furthermore, CaMKII is a key protein kinase in neural plasticity and memory. Here, we will introduce a selective and potent inhibitor of CaMKII, KN-62.

KN-62 is a Selective CaMKII Inhibitor.

First of all, KN-62 is a selective and potent inhibitor of CaMKII with an IC₅₀ of 0.9 μM. Meanwhile, KN-62 also displays noncompetitive antagonism at P2X₇ receptors in HEK293 cells, with an IC₅₀ value of approximately 15 nM.

In the second place, KN-62 potently antagonizes ATP-stimulated Ba²⁺ influx into fura-2 loaded human lymphocytes with an IC₅₀ of 12.7 nM. Interestingly, it has complete inhibition of the flux at a concentration of 500 nM. KN-62 does not inhibit the activity of autophosphorylated Ca2+/CaM kinase II. Importantly, KN-62 inhibited the Ca2+/calmodulin-dependent autophosphorylation of both alpha and beta subunits. In human leukemic B lymphocytes, KN-62 reduces the rate of permeability increase to larger permeant cations, like ethidium, induced by Bz-ATP with an IC₅₀ of 13.1 nM.

Last but not the least, KN62 significantly reduces the liver metastatic tumor burden in five weeks old BALB/c athymic nude mice inoculated with TAMR-MCF-7 cells. Particularly, KN-62 prevents the antidepressant-like behavior and antidepressant-like behaviors of ZnCl₂.

All in all, KN-62 is a selective and potent inhibitor of CaMKII.

References:

Gargett CE, et al. Br J Pharmacol. 1997 Apr;120(8):1483-90.