SKI-606

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

To evaluate the in vivo efficacy of SKI-606, K562 tumors were implanted into nude mice and staged to 200-300 mgs. The animals were treated with a 75 mg/kg oral dose of SKI-606 twice a day for 10 days, resulting in tumor... 

Of all the 4-anilino-3-quinoHnecarbonitrile dual Src/Abl inhibitors, the most extensively profiled analog is SKI-606. Pharmacokinetics showed SKI-606 to have an oral bio availability in nude mice of 18% and a half-hfe of 8.6 hours with a large volume of distribution [122]. SKI-606 was active in several colon tumor xenograft models when dosed orally at 25-150 mg/kg daily for 21 days with no weight loss or overt toxicity noted in the animals. On the basis of its pre-clinical properties, SKI-606 entered clinical trials in 2004 for the treatment of solid tumors and will soon be entering trials for the treatment of CML. 

Abbas R, Hug BA, Leister C, Sonnichsen D (2012) A randomized, crossover, placebo- and moxifloxacin-controlled study to evaluate the effects of bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects, hit J Cancer 131 E304-E311... 

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