Bosutinib (SKI-606)

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.

Health-related quality of life during bosutinib (SKI-606) therapy in patients with advanced chronic myeloid leukemia after imatinib failure.[Pubmed:27045164]

Curr Med Res Opin. 2016 Aug;32(8):1325-34.

OBJECTIVES: The tyrosine kinase inhibitor (TKI) bosutinib has demonstrated activity in patients with advanced phase chronic myeloid leukemia (CML), but effects on health-related quality of life (HRQoL) remain unexplored. This study evaluated HRQoL in advanced CML patients receiving bosutinib in an ongoing phase 2 study following resistance or intolerance to prior imatinib therapy. METHODS: This analysis included data from 76 accelerated-phase (AP) and 64 blast-phase (BP) patients resistant/intolerant to prior imatinib with or without prior exposure to other TKIs. Patient-reported HRQoL assessments completed at baseline; weeks 4, 8, and 12; every 12 weeks thereafter; and at treatment completion included the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu); general health status was assessed using the 5-item EuroQol (EQ-5D) instrument and a visual analog scale (VAS). RESULTS: HRQoL at baseline was somewhat worse in BP versus AP CML patients. There was a significant improvement in the mean FACT-Leu Total scale at weeks 24, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, 48, and 96 in BP CML patients compared with baseline. EQ-5D Utility scores were stable throughout treatment in AP CML patients but significantly improved versus baseline in BP CML patients at weeks 4, 8, 12, and 36. Mean VAS scores were significantly improved at weeks 8, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, and 96 in BP CML patients. The lack of a comparison group limits attribution of improvements in HRQoL specifically to bosutinib treatment; potential bias due to non-ignorable dropout may limit the ability to generalize these findings to situations where durations of therapy exceed the 96-week follow-up duration of the present study. CONCLUSION: These findings suggest that bosutinib therapy is associated with improved HRQoL in advanced phase CML patients. CLINICAL TRIAL REGISTRATION: NCT00261846.

Health-related quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant chronic phase chronic myeloid leukemia.[Pubmed:22036634]

Leuk Res. 2012 Apr;36(4):438-42.

Understanding the impact of second-line tyrosine kinase inhibitor therapy on the health-related quality of life (HRQOL) of imatinib (IM)-resistant and IM-intolerant chronic phase chronic myeloid leukemia (CP CML) patients is important given the increased survival that comes with therapy. As part of a bosutinib single-arm phase 2 trial, 200 IM-resistant and 88 IM-intolerant CP CML patients' HRQOL was assessed prior to and throughout treatment with the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Little HRQOL impairment was demonstrated at baseline. Over the course of 96 weeks on bosutinib therapy, patients noted statistically significant and/or clinically meaningful improvements on several FACT-Leu scales.

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.[Pubmed:22065400]

Int J Cancer. 2012 Aug 1;131(3):E304-11.

Effects of therapeutic and supratherapeutic concentrations of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, on the corrected QT interval (QTc) in 60 healthy adults were assessed, according to ICH-E14 guidelines, in this 2-part, randomized, single-dose, double-blind, crossover, placebo- and open-label moxifloxacin-controlled study. Subjects received placebo, moxifloxacin and bosutinib 500 mg with food (therapeutic) in Part 1. In Part 2, subjects received placebo and bosutinib 500 mg plus ketoconazole (supratherapeutic). ANOVA compared baseline-adjusted QTc for bosutinib with placebo; and bosutinib plus ketoconazole with placebo plus ketoconazole. Primary endpoint was population-specific QT correction (QTcN). Secondary endpoints were Bazett QT correction (QTcB), Fridericia's formula QT correction (QTcF) and individual QT correction (QTcI). Upper bounds for 90% confidence intervals were <10 msec for the mean change in QTcN from placebo at all postdose time points, suggesting that mean therapeutic exposures (C(max) , 114 ng/mL; AUC, 2,330 ng . h/mL) and mean supratherapeutic exposures (C(max) , 326 ng/mL; AUC, 15,200 ng . h/mL) were not associated with QTc changes. Similar results were obtained for QTcB, QTcF and QTcI. No clinically relevant pharmacokinetic/pharmacodynamic relationship was observed between bosutinib concentrations and QTc. No subjects had QTcB, QTcF, QTcI or QTcN >450 msec or change from baseline >30 msec. In summary, therapeutic and supratherapeutic bosutinib exposures are not associated with QTc prolongation in healthy adults.

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL(+) leukemia cells.[Pubmed:25465126]

Leuk Res. 2015 Jan;39(1):65-71.

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells.[Pubmed:18483306]

Mol Cancer Ther. 2008 May;7(5):1185-94.

Src family kinase activity is elevated in many human tumors, including breast cancer, and is often associated with aggressive disease. We examined the effects of SKI-606 (bosutinib), a selective Src family kinase inhibitor, on human cancer cells derived from breast cancer patients to assess its potential for breast cancer treatment. Our results show that SKI-606 caused a decrease in cell motility and invasion of breast cancer cell lines with an IC50 of approximately 250 nmol/L, which was also the IC50 for inhibition of cellular Src kinase activity in intact tumor cells. These changes were accompanied by an increase in cell-to-cell adhesion and membrane localization of beta-catenin. By contrast, cell proliferation and survival were unaffected by SKI-606 at concentrations sufficient to block cell migration and invasion. Analysis of downstream effectors of Src revealed that SKI-606 inhibits the phosphorylation of focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk-associated substrate (p130Cas), with an IC50 similar to inhibition of cellular Src kinase. Our findings indicate that SKI-606 inhibits signaling pathways involved in controlling tumor cell motility and invasion, suggesting that SKI-606 is a promising therapeutic for breast cancer.

SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models.[Pubmed:15958584]

Cancer Res. 2005 Jun 15;65(12):5358-64.

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.

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.[Pubmed:12543790]

Cancer Res. 2003 Jan 15;63(2):375-81.

Constitutive tyrosine kinase activity of Bcr-Abl promotes proliferation and survival of chronic myelogenous leukemia (CML) cells. Inhibition of Bcr-Abl tyrosine kinase activity or signaling proteins activated by Bcr-Abl in CML cells blocks proliferation and causes apoptotic cell death. The selective Abl kinase inhibitor, STI-571 (marketed as Gleevec), is toxic to CML cells in culture, causes regression of CML tumors in nude mice, and is currently used to treat CML patients. Here we describe a p.o. active, dual Src/Abl kinase inhibitor with potent antiproliferative activity against CML cells in culture. This 4-anilino-3-quinolinecarbonitrile (SKI-606) ablates tyrosine phosphorylation of Bcr-Abl in CML cells and of v-Abl expressed in fibroblasts. SKI-606 inhibits phosphorylation of cellular proteins, including STAT5, at concentrations that inhibit proliferation in CML cells. Phosphorylation of the autoactivation site of the Src family kinases Lyn and/or Hck is also reduced by treatment with SKI-606. Once daily oral administration of this compound at 100 mg/kg for 5 days causes complete regression of large K562 xenografts in nude mice.

Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity.[Pubmed:11689083]

J Med Chem. 2001 Nov 8;44(23):3965-77.

Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC(50) = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of 1a led to 1c, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC(50) of 1.2 nM in the Src enzymatic assay, an IC(50) of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.