Inhibitors of the Ca2+/calmodulin-dependent protein kinase phosphatase family (CaMKP and CaMKP-N)

Abstract

multifunctional CaMKI, II, and IV. However, the lack of specific inhibitors of these phosphatases has hampered studies on these enzymes in vivo. In an attempt to obtain specific inhibitors, we searched inhibitory compounds and found that Evans Blue and Chicago Sky Blue 6B served as effective inhibitors for CaMKP. These compounds also inhibited CaMKP-N, but inhibited neither protein phosphatase 2C, another member of PPM family phosphatase, nor calcineurin, a typical PPP family phosphatase. The minimum structure required for the inhibition was 1-amino-8-naphthol-4-sulfonic acid.When Neuro2a cells cotransfected with CaMKIV and CaMKP-N were treated with these compounds, the dephosphorylation of CaMKIV was strongly suppressed, suggesting that these compounds could be used as potent inhibitors of CaMKP and CaMKP-N in vivo as well as in vitro.

Sanguinarine as a Potent and Specific Inhibitor of Protein Phosphatase 2Cin Vitroand Induces ApoptosisviaPhosphorylation of p38 in HL60 Cells

“…Several compounds have been reported to be PP2C (PPM1A) inhibitors based on virtual screening and modification of phosphate esters. 5,6) Cyclic phosphopeptide inhibits PP2C (Wip1 or PPM1D), and Evans Blue and its derivatives inhibit Ca 2þ /calmodulin-dependent protein kinase phosphatase (CaMKP) and its nuclear isoform CaMKP-N, which are PP2C members, 7,8) but little is known about more potent and specific inhibitors of PP2C, especially natural products.…”

An Active C-Terminally Truncated Form of Ca2+/Calmodulin-Dependent Protein Kinase Phosphatase-N (CaMKP-N/PPM1E)

“…In contrast, NaF (100 mM) and EDTA (10 mM) severely inhibited the phosphatase. It is interesting that ANDS, a CaMKP-specific inhibitor [18], did not inhibit the phosphatase activity of hCaMKP-N(1–559) even at 30  μ M, a concentration at which the rat CaMKP was strongly inhibited.…”

Identification and characterization of human Rad51 inhibitors by screening of an existing drug library

“…Nevertheless, CSB and analogs have been previously found to inhibit different proteins [21,36,[42][43][44]. Thus, improvements of their inhibitor potency on Rad51 are necessary so that they might be specific enough to the recombinase protein for pharmacological studies on them.…”

“…Considering their chemical structure, these molecules could not easily enter the cell membranes, and so the nucleus, the site of Rad51 action. Nevertheless, Sueyoshi et al showed that CSB and compound 2 can be incorporated into cells to inhibit CaMKP-N expressed in those cells [36]. After verification, if CSB could not be used in its present form to improve cancer treatment, it may be a potential lead compound for developing Rad51-specific anticancer drugs.…”

“…Moreover, the removal of these dyes from effluents becomes a major environmental problem of the textile industry. Considering their potent inhibitory effect on the activity of crucial proteins such as Rad51 highlighted hereby but also other proteins [21,36,42,43], care must be taken in the use of these dyes for clinical or biochemical purposes.…”