Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ

Abstract

Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo-1) is a unique PKC activator with little tumor-promoting activities. Bryo-1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo-1-related compounds have been developed, the identification of synthetically more accessible compounds with bryo-1-like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo-1's unique mechanism of activating PKCδ that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog-1) of the tumor-promoting aplysiatoxin showed PKCδ-activating behavior similar to bryo-1. Aplog-1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor-promoting activity in vitro was very weak, and its cell growth-inhibitory activities were comparable to those of bryo-1. These data suggest that aplog-1 could become another therapeutic lead for cancer.

Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

“…The ability of PKC agonists to induce proteasomal degradation of PKC␣ indicates that the destabilizing effects of Hsp70/Hsc70 eventually override the protective effects of these chaperones, even in the presence of Hsp90 activity. The interaction between Hsp and PKC families described here is likely to have important implications for disorders such as cancer, HIV/ AIDS, neurodegenerative diseases, and inflammatory bowel disease, which (a) have been linked to aberrant chaperone expression/function (90 -92), (b) show altered degradation of activated PKC␣ and other PKC family members (3,(15)(16)(17)(18)(19)(20)22), and (c) are currently being evaluated as candidates for PKC agonist-based therapies (21,74,84,93).…”

Artificial Analogs of Naturally Occurring Tumor Promoters as Biochemical Tools and Therapeutic Leads

“…[89][90][91][92] The similarity of DAT and Bryo-1 in their lack of correlation between PKC binding and tumor-promoting activities prompted us to generate conceptually novel ATX analogs with Bryo-1-like activities. [93][94][95] Since ATX and DAT differ in their chemical structures only by the presence or absence of a bromine atom, decreased hydrophobicity due to the lack of a bromine atom might be responsible for the selective reduction in the tumor-promoting activity of DAT. Hence, in our initial analog design, 93) the hydrophobic methyl groups were replaced with a less hydrophobic hydrogen atom in an effort to realize further reduction in the tumor-promoting activity of DAT.…”

Screening for Protein Kinase C Ligands Using Fluorescence Resonance Energy Transfer

“…13) Various synthetic PKC ligands targeting the C1 domain have been developed as chemical probes or drug candidates by radioisotope assays. [14][15][16][17] We have previously developed a fluorescent assay for PKC-ligand binding affinity using a synthetic PKC δC1b domain labeled with a solvatochromic fluorophore on the edge of its ligand-binding pocket. This can detect ligand binding through changes in the surrounding environment.…”