ll-z1640-2 and monorden

While resorcylic acid lactones (RALs) have been known for a long time, the more recent discoveries that radicicol is a potent and selective HSP90 inhibitor while other members such as hypothemycin, LL-Z1640-2 and LL-783,277 are potent kinase inhibitors have stimulated a renewed interest in this family of natural products. The recent developments regarding the chemistry and biology of RALs are reviewed.

Topics: HSP90 Heat-Shock Proteins; Hydroxybenzoates; Lactones; Macrocyclic Compounds; Macrolides; Mitogen-Activated Protein Kinases; Molecular Structure; Mycotoxins; Zearalenone

Macrocyclic nonaketide compounds, radicicol and its two analogues, 87-250904-F1 and LL-Z1640-2, have various biological activities. Here we show that these compounds inhibit signal-dependent transcriptional activation with different specificity with distinct mechanism. Although all three compounds inhibited PMA-induced AP-1 transcriptional activity in cell-based reporter assay, these compounds exhibited differential effects in separate transcriptional reporter assays for NF-kappaB and glucocorticoid receptor. Next we found that one of these compounds, LL-Z1640-2, was a signal-specific inhibitor of the JNK/p38 pathways. In contrast to LL-Z1640-2, radicicol and 87-250904-F1 did not inhibit JNK/p38 activation. Recently, radicicol was reported as an inhibitor of activated-Ras-induced ERK activation. These results indicated that radicicol and LL-Z1640-2 showed distinct specificity to various MAP kinase pathways despite their structural similarity. Furthermore, LL-Z-1640-2 inhibited anisomycin-induced but not TNF-induced JNK/p38 activation, indicating that the inhibition mechanism is signal-specific.

Topics: 3T3 Cells; Activating Transcription Factor 2; Animals; Anisomycin; Anti-Bacterial Agents; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; Cyclic AMP Response Element-Binding Protein; Gene Expression; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; Lactones; Macrolides; Mice; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-jun; Receptors, Glucocorticoid; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transcription Factors; Transfection; Tumor Necrosis Factor-alpha