TAN-1813, a novel Ras-farnesyltransferase inhibitor produced by Phoma sp. taxonomy, fermentation, isolation and biological activities in vitro and in vivo.
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.
Ishii
T
T
Pharmaceutical Discovery Research Division, Takeda Chemical Industries, Ltd., Tsukuba, Ibaraki, Japan.
Hayashi
K
K
Hida
T
T
Yamamoto
Y
Y
Nozaki
Y
Y
D016475:3T3 Cells / Q000187:drug effects; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000935:Antifungal Agents; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001203:Ascomycota / Q000145:classification / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004352:Drug Resistance, Microbial / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D005285:Fermentation; D006801:Humans; D008297:Male; D008301:Maleimides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009154:Mutation; D009761:Nystatin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008301:Maleimides; C416813:TAN 1813; D009761:Nystatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins