Inhibition profiles for

Our initial findings that NPI-0052 inhibited all three proteolytic functions of the IDS proteasome vide supra) led us to compare its profile with other proteasome inhibitors (Figure 12.1) such as bortezomib,14 carfilzomib (PR-171)31 and CEP-187 70.30 These agents inhibit the CT-L activity to a similar degree as NPI-0052 but exhibit different inhibition profiles for the T-L and C-L activities. In addition, NPI-0052 exhibits a different recovery profile of proteasome functions in whole blood, normal organs, tumour and peripheral blood mononuclear cell preparations compared with other agents.52... 

Table 2. Signal Transduction Enzyme Inhibition Profiles for Microbial Extracsts...

Figure I. Inhibition profiles for strongly inhibitory carbamates. Data points are...

Figure 4. Inhibition profiles for oxon-containing organophosphorus insecticides. Data points are means, n= 3.

The inhibition profiles for dimethoate (parent compound), dimethoate-oxon and the bromine oxidized parent compound are shown in Figure 6. In this case, the inhibition profiles for the commercially available dimethoate-oxon and bromine oxidized parent compound were similar, suggesting that the bromine oxidation was nearly complete. It is interesting to note that dimethoate-oxon did not show the sigmoidal shape characteristic of most compounds but rather showed an almost log-linear profile. 

In an ideal circumstance, the inhibition curves for the compounds of interest would be identically shaped and placed along the abscissa (log concentration scale) at various positions depending on their relative IC50 values. Although the inhibition profiles for different compounds are often similar in shape, we have observed that a number of these curves do not show characteristic sigmoidal shape or similar slopes at their IC50 concentrations. Consequently, we investigated the inhibition profile for a mixture of five commonly used insecticides. 

A mixture of equimolar concentrations of chlorpyrifos, diazinon, dichlorvos, malathion and parathion (which sum to the plotted concentrations) was analyzed by this assay using the bromine oxidation protocol. Shown in Figure 7 are the inhibition profiles for paraoxon and the previously described mixture. Over a limited concentration range (i.e., 0.1 nM and above), the inhibition profile of the mixture is similar in shape to the paraoxon curve with paraoxon showing greater inhibition than the mixture. At concentrations below 0.1 nM, the curve deviates from its typical shape and the mixture appears to inhibit to a greater extent than paraoxon. This feature in the inhibition profile (i.e., the plateau in the activity at about 80% of maximum at low compound concentrations) was also observed with chlorpyrifos-oxon (see Figure 5). 

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