Bosutinib (SKI-606) is a potent inhibitor of Src and Abl kinases with IC50 of 1.2 nM and 1 nM [1].
In chronic myelogenous leukemia (CML) cells, SKI-606 inhibited phosphorylation of Bcr-Abl, Src and Stat5. It also ablated the expression of v-Abl in fibroblasts and blocked proliferation of CML cells [2]. In colorectal cancer cells, SKI-606 inhibited Src autophosphorylation with an IC50 of ~ 0.25 μM, and simultaneity suppressed Tyr (925) phosphorylation of a Src substrate [3]. SKI-606 blocked beta-catenin function by inhibiting its binding to the TCF4 transcription factor and dose-dependently suppressed cyclin D1. SKI-606 increased its binding affinity of beta-catenin to E-cadherin and adhesion, with ensuing reduced motility in a wound healing assay [4].
Oral administration of SKI-606 at 100 mg/kg for 5 days causes complete regression of large K562 xenografts in nude mice [2].
[1]. Boschelli DH, Ye F, Wang YD, Dutia M, Johnson SL, Wu B, Miller K, Powell DW, Yaczko D, Young M, Tischler M, Arndt K, Discafani C, Etienne C, Gibbons J, Grod J, Lucas J, Weber JM, Boschelli F. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem. 2001 Nov 8;44(23):3965-77.
References:
[2]. Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, Frost P, Ye F, Boschelli DH, Boschelli F. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003 Jan 15;63(2):375-81.
[3]. Golas JM, Lucas J, Etienne C, Golas J, Discafani C, Sridharan L, Boghaert E, Arndt K, Ye F, Boschelli DH, Li F, Titsch C, Huselton C, Chaudhary I, Boschelli F. SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Cancer Res. 2005 Jun 15;65(12):5358-64.
[4]. Coluccia AM, Benati D, Dekhil H, De Filippo A, Lan C, Gambacorti-Passerini C. SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Cancer Res. 2006 Feb 15;66(4):2279-86.