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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Departments of 1 Oncology, 2 Chemical and Screening Sciences, and 3 Drug Safety and Metabolism, Wyeth Research, Pearl River, New York
Requests for reprints: Frank Boschelli, Department of Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965. Phone: 845-602-5439; Fax: 845-602-5557; E-mail: boschef{at}wyeth.com.
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 IC50 of 
0.25 µmol/L in HT29 cells. Phosphorylation of Tyr925 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 (IC50s, 1.5 and 2.5 µmol/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 3 µmol/L, an oral bioavailability of 18%, and a t1/2 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 Tyr418 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.
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