A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies.
Ras mutation has been detected in approximately 20-30% of all human carcinomas, primarily in pancreatic, colorectal, lung and bladder carcinomas. The indirect inhibition of Ras activity by inhibiting farnesyltransferase (FTase) function is one therapeutic intervention to control tumor growth. Here we report the preclinical anti-tumor activity of our most advanced FTase inhibitor (FTI), ABT-100, and a direct comparison with the current clinical candidates. ABT-100 is a highly selective, potent and orally bioavailable FTI. It broadly inhibits the growth of solid tumors in preclinical animal models. Thus, ABT-100 is an attractive candidate for further clinical evaluation. In addition, our results provide plausible insights to explain the impressive potency and selectivity of ABT-100. Finally, we have demonstrated that ABT-100 significantly suppresses the expression of vascular endothelial growth factor (VEGF) mRNA and secretion of VEGF protein, as well as inhibiting angiogenesis in the animal model.
Gu
Wen-Zhen
WZ
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Joseph
Ingrid
I
Wang
Yi-Chun
YC
Frost
David
D
Sullivan
Gerard M
GM
Wang
Le
L
Lin
Nan-Horng
NH
Cohen
Jerry
J
Stoll
Vincent S
VS
Jakob
Clarissa G
CG
Muchmore
Steven W
SW
Harlan
John E
JE
Holzman
Tom
T
Walten
Karl A
KA
Ladror
Uri S
US
Anderson
Mark G
MG
Kroeger
Paul
P
Rodriguez
Luis E
LE
Jarvis
Kenneth P
KP
Ferguson
Debra
D
Marsh
Kennan
K
Ng
Shichung
S
Rosenberg
Saul H
SH
Sham
Hing L
HL
Zhang
Haiying
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016510:Corneal Neovascularization / Q000188:drug therapy; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000037:antagonists & inhibitors*
C503142:ABT-100; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051231:Farnesyltranstransferase; D018631:ras Proteins