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Chemical Compound Review:

ABT-100 4-[(2S)-2-(4-cyanophenyl)-2- hydroxy-2-(3...

Synonyms: ABT100, SureCN2731728, ABT 100, AC1O52UD, A-409100, ...

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Disease relevance of ABT 100

Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent [1].
We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria [2].

High impact information on ABT 100

RESULTS: ABT-100 inhibited proliferation of cells in vitro carrying oncogenic H-Ras (EJ-1 bladder; IC(50) 2.2 nmol/L), Ki-Ras (DLD-1 colon, MDA-MB-231 breast, HCT-116 colon, and MiaPaCa-2 pancreatic; IC(50) range, 3.8-9.2 nmol/L), and wild-type Ras (PC-3 and DU-145; IC(50), 70 and 818 nmol/L, respectively) as well as clonogenic potential [3].
PURPOSE: To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100 [3].
RESULTS: ABT-100 inhibited HepG2 and Huh7 cell growth as well as the invading ability of Huh7 on Matrigel [1].
Furthermore, ABT-100 inhibited Akt-dependent p27(Kip1) phosphorylation and this event was associated with increased levels of p27(Kip1) in the nucleus and reduced activity of the cyclin-dependent kinase 2 [1].
ABT-100 shows 70% to 80% oral bioavailability in mice [3].

Biological context of ABT 100

In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics [3].

Anatomical context of ABT 100

EXPERIMENTAL DESIGN: In the present study, we investigated the effects of a novel farnesyltransferase inhibitor, ABT-100, on human liver cancer cell lines, HepG2 and Huh7, and on an animal model of hepatocarcinogenesis [1].
METHODS: The effects of ABT-100 on human peripheral blood mononuclear cell (PBMC) proliferation and the expression of the T cell activation markers CD25 and CD69 were studied [4].

Gene context 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 [5].
RESULTS: ABT-100 potently inhibited PBMC proliferation, but did not decrease expression of CD25 and CD69 during activation [4].
CONCLUSIONS: Taken together, these findings identify a mechanism of ABT-100 function and show the efficacy of ABT-100 as a chemopreventive agent of hepatocellular carcinoma [1].

Analytical, diagnostic and therapeutic context of ABT 100

Treatment with 25, 50 and 100 mg/kg ABT-100 BID increased allograft mean survival time (MST) to 12.8+/-3 days, 13.5+/-5 days and 13.8+/-3 days, respectively (vs 6.5+/-3 days for controls, p<0.001 by log rank) [4].

References

Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent. Carloni, V., Vizzutti, F., Pantaleo, P. Clin. Cancer Res. (2005) [Pubmed]
A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Fong, L.G., Frost, D., Meta, M., Qiao, X., Yang, S.H., Coffinier, C., Young, S.G. Science (2006) [Pubmed]
Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models. Ferguson, D., Rodriguez, L.E., Palma, J.P., Refici, M., Jarvis, K., O'Connor, J., Sullivan, G.M., Frost, D., Marsh, K., Bauch, J., Zhang, H., Lin, N.H., Rosenberg, S., Sham, H.L., Joseph, I.B. Clin. Cancer Res. (2005) [Pubmed]
Potent farnesyltransferase inhibitor ABT-100 abrogates acute allograft rejection. Si, M.S., Ji, P., Lee, M., Kwok, J., Kusumoto, J., Naasz, E., Ng, S.C., Imagawa, D.K. J. Heart Lung Transplant. (2005) [Pubmed]
A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies. Gu, W.Z., Joseph, I., Wang, Y.C., Frost, D., Sullivan, G.M., Wang, L., Lin, N.H., Cohen, J., Stoll, V.S., Jakob, C.G., Muchmore, S.W., Harlan, J.E., Holzman, T., Walten, K.A., Ladror, U.S., Anderson, M.G., Kroeger, P., Rodriguez, L.E., Jarvis, K.P., Ferguson, D., Marsh, K., Ng, S., Rosenberg, S.H., Sham, H.L., Zhang, H. Anticancer Drugs (2005) [Pubmed]

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