Identification of Ras farnesyltransferase inhibitors by microbial screening.
A microbial screen using a yeast strain with conditional deficiency in the GPA1 gene was carried out to search for inhibitors of protein farnesyltransferase (PFT). A strain of Streptomyces was found to produce active compounds named UCF1-A, UCF1-B, and UCF1-C. Structural determination of these compounds revealed that UCF1-C is identical to the known antibiotic, manumycin, whereas UCF1-A and UCF1-B are structurally related to manumycin. All three UCF1 compounds suppress the lethality of gpa1 disruption, with UCF1-C exhibiting the strongest activity. UCF1 inhibits yeast as well as rat brain PFT. Fifty percent inhibition of yeast PFT activity is observed with 5 microM UCF1-C. Kinetic analyses of the inhibition suggest that UCF1-C acts as a competitive inhibitor of PFT with respect to farnesyl pyrophosphate, exhibiting a Ki of 1.2 microM, whereas the same compound appears to act as a noncompetitive inhibitor of PFT with respect to the farnesyl acceptor, the Ras protein. UCF1-C shows significant activity to inhibit the growth of Ki-ras-transformed fibrosarcoma, raising the possibility of its use as an antitumor drug.
Hara
M
M
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
Akasaka
K
K
Akinaga
S
S
Okabe
M
M
Nakano
H
H
Gomez
R
R
Wood
D
D
Uh
M
M
Tamanoi
F
F
D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000201:enzymology; D002417:Cattle; D002471:Cell Transformation, Neoplastic; D005354:Fibrosarcoma / Q000188:drug therapy*; D005800:Genes, Fungal; D005804:Genes, Lethal / Q000187:drug effects; D011905:Genes, ras; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011090:Polyenes / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D013302:Streptomyces / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011993:Recombinant Fusion Proteins; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D005982:Glutathione Transferase; C054474:manumycin