title: SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models.
abstract: 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.
authors.affiliation: Department of Oncology, Wyeth Research, Pearl River, New York 10965, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Golas
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Carlo
authors.initials: C
authors.lastname: Etienne
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golas
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
authors.forename: Latha
authors.initials: L
authors.lastname: Sridharan
authors.forename: Erwin
authors.initials: E
authors.lastname: Boghaert
authors.forename: Kim
authors.initials: K
authors.lastname: Arndt
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: Fangbiao
authors.initials: F
authors.lastname: Li
authors.forename: Craig
authors.initials: C
authors.lastname: Titsch
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D019061:src-Family Kinases