Protein Kinase C (PKC) Inhibitors

Protein kinase C (PKC), a ubiquitous, phospholipid-dependent enzyme, is involved in signal transduction associated with cell proliferation, differentiation, and apoptosis. At least eleven closely related PKC isozymes have been reported that differ in their structure, biochemical properties, tissue distribution, subcellular localization, and substrate specificity. They are classified as conventional (α, β1, β2, γ), novel (δ, ε, η, θ, μ), and atypical (ζ, λ) isozymes. Conventional PKC isozymes are Ca²⁺-dependent, while novel and atypical isozymes do not require Ca²⁺ for their activation. All PKC isozymes, with the exception of ζ and λ, are activated by diacylglycerol (DAG). PKC isozymes negatively or positively regulate critical cell cycle transitions, including cell cycle entry and exit and the G₁ and G₂ checkpoints.

All PKC isoforms show different distribution among various cells. The α, δ, and ζ isoforms are found in all cells. The γ isoform is found only in neuronal cells. The η, ε, and λ isoforms are found in various tissues, whereas η and τ isoforms are predominantly found in epithelial and immune cells.

In its unstimulated state, most of the PKC resides in the cytosol. In this state, the pseudosubstrate sequence of the regulatory domain of PKC interacts with the catalytic domain and prevents access of the substrate to the catalytic site. Binding of a hormone or other effector molecule to the membrane receptor results in activation of phospholipase C (PLC) or phospholipase A₂ (PLA₂) via a G-protein-dependent phenomenon. The activated PLC hydrolyzes phosphatidylinositol-4, 5-bisphosphate (PIP₂) to produce DAG and inositol- 1,4,5-trisphosphate (IP₃). The IP₃ causes the release of endogenous Ca²⁺ that binds to the cytosolic PKC and exposes the phospholipidbinding site. The binding of Ca²⁺ translocates PKC to the membrane, where it interacts with DAG and is transformed into a fully active enzyme.

Altered PKC activity has been linked with various types of malignancies. Higher levels of PKC and differential activation of various PKC isozymes have been reported in breast tumors, adenomatous pituitaries, thyroid cancer tissue, leukemic cells, and lung cancer cells. Downregulation of PKC_α is reported in the majority of colon adenocarcinomas and in the early stages of intestinal carcinogenesis. Thus, PKC inhibitors have become important tools in the treatment of cancers. The involvement of PKC in the regulation of apoptosis adds another dimension to the effort to develop drugs that will specifically target PKC.

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Specific Protein Kinase C (PKC) Inhibitors