Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM-46228.
Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a wide spectrum of human cancers (pancreas, thyroid, colon, non-small-cell lung cancer). Membrane anchorage of Ras, required for functional activity in signal transduction, is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel FTase inhibitor, BIM-46228, which showed (i) specific inhibition of purified human FTase enzyme, (ii) inhibition of proliferation in vitro in a large spectrum of human tumor cell lines, (iii) inhibition of growth of human tumor xenografts in athymic nude mice treated by per os administration and (iv) the benefits of in vitro combination of its activity with chemotherapy or radiotherapy.
Institut Henri Beaufour, Les Ulis, France. gregoire.prevost@beaufour-ipsen.com
G P
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Prevost
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A
Pradines
M C
MC
Brezak
M O
MO
Lonchampt
I
I
Viossat
I
I
Ader
C
C
Toulas
P
P
Kasprzyk
T
T
Gordon
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Favre
B
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Morgan
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D002455:Cell Division; D003131:Combined Modality Therapy; D004122:Dimethylallyltranstransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D009570:Nitriles / Q000737:chemistry / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C423822:BIM 46228; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D010455:Peptides; C012258:mevastatin; D008148:Lovastatin; D019883:Alkyl and Aryl Transferases; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase; D017239:Paclitaxel