SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models
Open accessAbstract
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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Bosutinib, an oral Src/Abl inhibitor, abrogates c-src and FAK autophosphorylation in HT-29 cells, attenuates tumor growth in various CRC cell lines, and is active in injected nude mice.
“bosutinib, another oral Src/Abl inhibitor, which abrogated c-src and FAK autophosphorylation in HT-29 cells, attenuated tumor growth in various CRC cell lines and was found to be also active in injected nude mice.81”
From The molecular rationale of Src inhibition in colorectal carcinomas (2014) · cites this paper as [81]
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- Authors
- 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.
- Affiliations
- 1Oncology, Departments of
- 2Chemical and Screening Sciences, and
- Wyeth (US)
- Venue
- Cancer Research
- Published
- 2005-06-15
- Volume
- 65
- Issue
- 12
- Pages
- 5358-5364
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2118688827
- Cited by
- 134
- References
- 53
- Citations by year
- 2024: 1 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 7 · 2013: 6 · 2012: 6
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- Src kinase inhibitor, ABL kinase inhibitors, colorectal cancer, focal adhesion kinase phosphorylation, oral bioavailability, tumor growth inhibition, antiproliferative activity, kinase inhibitors
- MeSH terms
- Administration, Oral, Aniline Compounds, Animals, Antineoplastic Agents, Colonic Neoplasms, Female, Humans, Mice, Nude, Nitriles, Phosphorylation, Quinolines, src-Family Kinases, HT29 Cells, Xenograft Model Antitumor Assays, HCT116 Cells, Protein Kinase Inhibitors, Mice
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