SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models

Src up-regulation is a common event in human cancers. In colorectal cancer, increased Src levels are an indicator of poor prognosis, and progression to metastatic disease is associated with substantial increases in Src activity. Therefore, we examined the activity of SKI-606, a potent inhibitor of S...

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Published in:	Cancer research (Chicago, Ill.) Vol. 65; no. 12; pp. 5358 - 5364
Main Authors:	GALAS, Jennifer M, LUCAS, Judy, FANGBIAO LI, TITSCH, Craig, HUSELTON, Christine, CHAUDHARY, Inder, BOSCHELLI, Frank, ETIENNE, Carlo, GOLAS, Jonathan, DISCAFANI, Carolyn, SRIDHARAN, Latha, BOGHAERT, Erwin, ARNDT, Kim, FEI YE, BOSCHELLI, Diane H
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-06-2005
Subjects:	Administration, Oral Aniline Compounds - pharmacokinetics Aniline Compounds - pharmacology Animals Antineoplastic agents Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Biological and medical sciences Colonic Neoplasms - drug therapy Colonic Neoplasms - enzymology Colonic Neoplasms - metabolism Female HCT116 Cells HT29 Cells Humans Medical sciences Mice Mice, Nude Nitriles - pharmacokinetics Nitriles - pharmacology Pharmacology. Drug treatments Phosphorylation - drug effects Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Quinolines - pharmacokinetics Quinolines - pharmacology src-Family Kinases - antagonists & inhibitors Tumors Xenograft Model Antitumor Assays Digestive system Enzyme Transferases Gut Activity Malignant tumor Heterograft Heterotransplantation In vivo Inhibitor Models Colon Protein-tyrosine kinase
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Summary:	Src up-regulation is a common event in human cancers. In colorectal cancer, increased Src levels are an indicator of poor prognosis, and progression to metastatic disease is associated with substantial increases in Src activity. Therefore, we examined the activity of SKI-606, a potent inhibitor of Src and Abl kinases, against colon tumor lines in vitro and in s.c. tumor xenograft models. SKI-606 inhibited Src autophosphorylation with an IC(50) of approximately 0.25 micromol/L in HT29 cells. Phosphorylation of Tyr(925) of focal adhesion kinase, a Src substrate, was reduced by similar concentrations of inhibitor. 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. SKI-606 also caused loosely aggregated Colo205 spheroids to condense into compact spheroids. On oral administration to nude mice at the lowest efficacious dose, peak plasma concentrations of approximately 3 micromol/L, an oral bioavailability of 18%, and a t(1/2) of 8.6 hours were observed. 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. SKI-606 inhibited HT29 tumor growth on once daily administration, whereas twice daily administration was necessary to inhibit Colo205, HCT116, and DLD1 tumor growth. These results support development of SKI-606 as a therapeutic agent for treatment of colorectal cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-04-2484