The clinical trials with enzastaurin have been promising . In the various Fostamatinib studies, the drug has been well tolerated with few severe side effects reported. Among the 55 patients in the diffuse large B cell lymphoma study conducted by Robertson et al. , there were no deaths reported and only one patient suffered hypomagnesemia . Importantly, the drug was effective at delaying disease progression in a number of the patients and three patients exhibited complete responses . PKC activity in general has been associated with resistance to therapy in AML so targeting PKC would be useful for AML therapy. Enzastaurin at high doses may be most effective in combination with other AML therapeutic drugs as a means to suppress PKC a and suppress BCL2 anti apoptotic activity.
Enzastaurin small molecule Bcr-Abl inhibitor has been used successfully in combination with paclitaxel and other chemotherapeutic agents in mouse xenograft models . Enzastaurin was found to suppress phosphorylation of a distinct set of proteins . These proteins likely represent targets of PKC a or b or a kinase that is regulated by PKC. An example of a prosurvival kinase that is suppressed by enzastaurin inhibition of PKC is AKT . In addition, PKC a has been found to negatively regulate the PP2A isoform that serves as the BCL2 phosphatase and promotes apoptosis in acute leukemia cells . It is possible that enzastaurin promotes asenapine clinical trial activation of this PP2A isoform to suppress protein phosphorylation. The finding that the drug was effective at suppressing BCL2 phosphorylation supports this notion.
It was also found that enzastaurin promoted phosphorylation of a distinct set of proteins . If enzastaurin supports activation of a specific PP2A isoform, Pimecrolimus solubility then it is plausible that other PP2A isoforms will be suppressed since there is a competition between PP2A B subunits to associate with the enzyme’s catalytic core . Perhaps the proteins displaying increased phosphorylation are the substrates of PP2A isoforms that compete with the PP2A subunit containing PPP2R5A. However, it is premature to implicate PP2A in this phenomenon as one cannot rule out the effect of the drug on non PP2A protein phosphatases. In summary, enzastaurin was found to be effective at killing AML derived cells from cell lines and from primary blasts though by a mechanism that likely does not involve the inhibition of PKC b.
The drug suppressed PKC a phosphorylation and localization and blocked activation fetal rights of ERK and phosphorylation of BCL2. It is possible that enzastaurin promotes activation of a protein phosphatase that would be negatively regulated by PKC. These results suggest that enzastaurin could have clinical anti leukemia activity in AML.Dysregulation of the protein kinase C signaling pathway has been implicated in tumor progression. In this study, we investigate the effects of a PKC inhibitor, Enzastaurin, in human pancreatic neuroendocrine neoplasms primary cultures and in the human pancreatic endocrine cancer cell line, BON1. To this aim six human PNN dispersed in primary cultures and BON1 cells were treated without or with 1 10 mMEnzastaurin and/or 100 nM IGF1 in the presence or absence of serum. Cell viability and apoptosis were evaluated after 48 72 h; Chromogranin A and/or insulin secretion was assessed after 6 h.