Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Javascript disabled

Please enable Javascript support in your browser to use this application.

Instructions on how to enable JavaScript on different browsers can be found here: http://www.google.com/support/bin/answer.py?answer=23852.

[edit this page]

Chemical Compound Review:

K00615a 4-[(2,4-dichloro-5-methoxy- phenyl)amino]-6...

Coluccia, A.M., Golas, J.M., Golas, J.M., Puttini, M., Zhang, J., et al.

Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text.

Ideally this entry shall become one comprehensive and continuous article. Bulleted lists, for instance, were only used because it is impossible to automatically integrate independent facts into a continuous text.

Much of the current information on this page has been automatically compiled from Pubmed.

This precompiled information serves as a substrate and matrix to embed your contributions, but it is by no means the final word - Homo sapiens can do much better!

WikiGenes is a non-profit and open access community project.

Disease relevance of SKI-606

These results support development of SKI-606 as a therapeutic agent for treatment of colorectal cancer [1].
SKI-606 proved to be an active inhibitor of Bcr-Abl in several chronic myelogenous leukemia cell lines and transfectants, with IC(50) values in the low nanomolar range, 1 to 2 logs lower than those obtained with imatinib [2].

High impact information on SKI-606

The SKI-606-mediated relocalization of beta-catenin increased its binding affinity to E-cadherin and adhesion of colorectal cancer cells, with ensuing reduced motility in a wound healing assay [3].
SKI-606 retained activity in cells where resistance to imatinib was caused by BCR-ABL gene amplification and in three of four Bcr-Abl point mutants tested [2].
Src-dependent activation of beta-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated beta-catenin nuclear function by impairing its binding to the TCF4 transcription factor and its trans-activating ability in colorectal cancer cells [3].
SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling [3].
In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells [2].

Biological context of SKI-606

SKI-606 inhibits phosphorylation of cellular proteins, including STAT5, at concentrations that inhibit proliferation in CML cells [4].
These effects were seemingly specific, as cyclin D1, a crucial beta-catenin/TCF4 target gene, was also down-regulated by SKI-606 in a dose-dependent manner accounting, at least in part, for the reduced growth (IC50, 1.5-2.4 micromol/L) and clonogenic potential of colorectal cancer cells [3].
The EGFR-dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs, and treatment of these cells with an SFK inhibitor (PP1 or SKI-606) induced apoptosis [5].
One of the potent c-Src and c-Abl dual kinase inhibitors (77 or SKI-606) was docked inside the active sites of both c-Src and c-Abl [6].

Anatomical context of SKI-606

Antiproliferative activity on plastic did not correlate with Src inhibition in either HT29 or Colo205 cells (IC(50)s, 1.5 and 2.5 micromol/L, respectively), although submicromolar concentrations of SKI-606 inhibited HT29 cell colony formation in soft agar [1].
This 4-anilino-3-quinolinecarbonitrile (SKI-606) ablates tyrosine phosphorylation of Bcr-Abl in CML cells and of v-Abl expressed in fibroblasts [4].

Associations of SKI-606 with other chemical compounds

One of the analogues reported here exhibited in vivo activity comparable to that of SKI-606, a related 3-quinolinecarbonitrile currently in clinical trials [7].

Gene context of SKI-606

SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice [4].
SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models [1].

Analytical, diagnostic and therapeutic context of SKI-606

SKI-606 was orally active in s.c. colon tumor xenograft models and caused substantial reductions in Src autophosphorylation on Tyr(418) in HT29 and Colo205 tumors [1].
Protein levels of beta-catenin remained substantially unchanged by SKI-606, which promoted instead a cytosolic/membranous retention of beta-catenin as judged by immunoblotting analysis of cytosolic/nuclear extracts and cell immunofluorescence staining [3].
Compound 17d was more potent in vitro than the analogously substituted 4-anilinoquinoline-3-carbonitrile SKI-606, which is undergoing evaluation in clinical trials [8].

References

SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Golas, J.M., Lucas, J., Etienne, C., Golas, J., Discafani, C., Sridharan, L., Boghaert, E., Arndt, K., Ye, F., Boschelli, D.H., Li, F., Titsch, C., Huselton, C., Chaudhary, I., Boschelli, F. Cancer Res. (2005)
In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells. Puttini, M., Coluccia, A.M., Boschelli, F., Cleris, L., Marchesi, E., Donella-Deana, A., Ahmed, S., Redaelli, S., Piazza, R., Magistroni, V., Andreoni, F., Scapozza, L., Formelli, F., Gambacorti-Passerini, C. Cancer Res. (2006)
SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Coluccia, A.M., Benati, D., Dekhil, H., De Filippo, A., Lan, C., Gambacorti-Passerini, C. Cancer Res. (2006)
SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Golas, J.M., Arndt, K., Etienne, C., Lucas, J., Nardin, D., Gibbons, J., Frost, P., Ye, F., Boschelli, D.H., Boschelli, F. Cancer Res. (2003)
SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Zhang, J., Kalyankrishna, S., Wislez, M., Thilaganathan, N., Saigal, B., Wei, W., Ma, L., Wistuba, I.I., Johnson, F.M., Kurie, J.M. Am. J. Pathol. (2007)
3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases. Thaimattam, R., Daga, P.R., Banerjee, R., Iqbal, J. Bioorg. Med. Chem. (2005)
Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles. Boschelli, D.H., Wu, B., Barrios Sosa, A.C., Durutlic, H., Chen, J.J., Wang, Y., Golas, J.M., Lucas, J., Boschelli, F. J. Med. Chem. (2005)
4-Anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles as potent Src kinase inhibitors. Berger, D.M., Dutia, M., Birnberg, G., Powell, D., Boschelli, D.H., Wang, Y.D., Ravi, M., Yaczko, D., Golas, J., Lucas, J., Boschelli, F. J. Med. Chem. (2005)