TAN-1813, a novel Ras-farnesyltransferase inhibitor produced by Phoma sp. taxonomy, fermentation, isolation and biological activities in vitro and in vivo.

Abstract

A novel Ras-farnesyltransferase inhibitor designated TAN-1813 was isolated from the culture broth of a fungus strain, FL-41510, isolated as a plant endophyte. The producer was taxonomically characterized as Phoma sp. FL-41510. TAN-1813 inhibited rat brain farnesyltransferase and geranylgeranyltransferase I activity with IC50 values of 23 microg/ml and 47/microg/ml, respectively. TAN-1813 showed mixed-type inhibition with respect to farnesylpyrophosphate and noncompetitive inhibition with respect to a K-Ras C-terminal peptide. It also inhibited the in situ farnesylation of cellular Ras proteins in a K-ras transformant (NIH3T3/K-ras) of mouse embryonic fibroblast cell line NIH3T3. TAN- 1813 inhibited the proliferation of various human cancer cells, some of which harbor activated ras alleles, with IC50 values of 15 approximately 110 ng/ml as well as that of NIH3T3 and NIH3T3/K-ras cells with IC50S of 540 and 310 ng/ml, respectively. Flow cytometric analysis indicated that TAN-1813 arrests NIH3T3/K-ras cells at both G1 and G2/M phases of the cell cycle. In addition, TAN-1813 was found to induce morphological reversion of NIH3T3/K-ras cells from the transformed phenotype. Antitumor activity of TAN-1813 against human fibrosarcoma HT-1080 and NIH3T3/K-ras tumors in nude mice was also verified.

• Authors: T Ishii, K Hayashi, T Hida, Y Yamamoto, Y Nozaki
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 53 Issue 8 Pg. 765-78 (Aug 2000) ISSN: 0021-8820 [Print] England
• PMID: 11079798 (Publication Type: Journal Article)

Chemical References

• Antifungal Agents
• Antineoplastic Agents
• Enzyme Inhibitors
• Maleimides
• TAN 1813
• Nystatin
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• p21(ras) farnesyl-protein transferase
• ras Proteins

Topics

• 3T3 Cells (drug effects)
• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Antifungal Agents
• Antineoplastic Agents (isolation & purification, pharmacology)
• Ascomycota (classification, metabolism)
• Cell Division (drug effects)
• Drug Resistance, Microbial (genetics)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (isolation & purification, metabolism, pharmacology)
• Fermentation
• Humans
• Male
• Maleimides (chemistry, metabolism, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Mice, Nude
• Mutation
• Nystatin (pharmacology)
• Rats
• Rats, Wistar
• Saccharomyces cerevisiae (drug effects, genetics)
• Tumor Cells, Cultured
• ras Proteins (genetics)