SKI-606 AGAINST SRC KINASES

by Selleckchem | Mar 13 2012

SKI-606: SRC Inhibitors

Tyrosine kinases are a subgroup of the protein kinase super family and have been shown to regulate cell growth pattern, cellular proliferation, angiogenesis, invasion and metastasis in mammalian tissues. Many tyrosine kinases are up-regulated in tumor progression and present potential targets for chemotherapeutic inhibition. The Src kinase is non-receptor tyrosine kinase that includes 3 sub-families (SrcA,SrcB and SrcC). SrcA sub family is made up of Src, Yes, Fyn, and Fgr proteins while SrcB is made Lck, Hckm Blk and Lyn proteins. It has been reported in several tumor types that Src levels are elevated and this rise continues with progression of the disease. Tne mechanism behind Src elevation is not clearly understood and it is theorized that is the product of a “multifactorial process”[1]. To further confuse the issue Src appears to changes its activity based on a direct or indirect interaction with EGFR[2], PDGFR [3], FGFR[4] , CSF-1R [5] , HER2 [6] or c-MET [7]. This interaction was confirmed when it was observed that EGFR and Scr expression in fibroblasts synergistically correlated to tumor progression rather than either Src or EGFR alone. Hence to inhibit Scr alone could be consider to be redundant but a multikinase inhibitor for Scr appeared attractive. SKI-606 is a dual inhibiting tyrosine kinase inhibitor. It is known to inhibit both Scr and ABL1 ( a cytoplasmic / nuclear tyrosine kinase). Abl1 is the regulatory protein that should maintain Scr expression but it is often mutated in tumor cells and Scr is completely unregulated. Hence a dual inhibitor has the potential of being a powerful tool for tumor chemotherapy.

Bosutinib (SKI-606) Chemical Structure

SKI-606: Properties and availability.

The SKI-606 SRC inhibitor is marketed under the trade name Bosutinib and is under development by Pfizer. SKI-606 structure clearly indicates that it is a substituted quinoline based molecule with activity for the ABL and SRC kinases. The SKI-606 IC50 for its targets are ABL1 (1.4 nM) and SRC (3.5 nM). SKI-606 solubility in water is extremely poor but SKI-606 is soluble in DMSO and ethanol, maximum concentrations are 33 mg/ml and 10 mg/ml respectively. SKI-606 stability is listed for its powdered free base and this can be stored for upwards of 2 years if kept at -20^oC or below. Researchers can buy SKI-606 free base or from a variety of SKI-606 suppliers although SKI-606 price is dependent on the supplier. The price of a 25 mg vial can range from $39 up to $360; researchers are advised to shop very carefully for this product.

SKI-606: CLINICAL Status

SKI-606 is a third generation tyrosine kinase inhibitor which is also classified as a histone deacetylase inhibitor (HDAC). Pre-clinical research has established that SKI-606 while inhibiting Scr and ABL1 it does also inhibit several other tyrosine kinases [8]. SKI-606 is the only reported small molecule to inhibit CAM2G which is a protein that is significantly involved in myeloid leukemia cell proliferation. As a result SKI-606 has been tested in both AML and CML type cells. Strong evidence of anti-tumor activity has been observed in vitro. Phase 1 trials were initiated very quickly and MTD was established as 500mg per day, orally taken. SKI-606 clinical trials demonstrated an immediate effect in patients resistant to the standard treatment (Imatinib, Nilotinib or Dasatinib) where 74 % of the patients resistant to Imatinib a complete response, disease free. Further investigation revealed that the Philadelphia chromosome had been completely deleted. Of the patients resistant to Nilotinib or Dasatinib 50% complete response rate was seen in, with deletion of the Philadelphia chromosome occurring in 20%.[8;9] In addition to AML and CML SKI-606 is also being phase 1/2 tested in breast cancer, Glioblastoma, polycystic kidney disease, advanced malignant solid tumors , prostate cancer and in pancreas cancer [10-13]

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References

1. Bolen JB, Veillette A et al. Analysis of pp60c-src in human colon carcinoma and normal human colon mucosal cells. Oncogene Res 1987; 1(2):149-168.

2. Tice DA, Biscardi JS et al. Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci U S A 1999; 96(4):1415-1420.

3. Courtneidge SA, Fumagalli S et al. The Src family of protein tyrosine kinases: regulation and functions. Dev Suppl 1993;57-64.

4. LaVallee TM, Prudovsky IA et al. Activation of the MAP kinase pathway by FGF-1 correlates with cell proliferation induction while activation of the Src pathway correlates with migration. J Cell Biol 1998; 141(7):1647-1658.

5. Courtneidge SA, Dhand R et al. Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor. EMBO J 1993; 12(3):943-950.

6. Luttrell DK, Lee A et al. Involvement of pp60c-src with two major signaling pathways in human breast cancer. Proc Natl Acad Sci U S A 1994; 91(1):83-87.

7. Rahimi N, Hung W et al. c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J Biol Chem 1998; 273(50):33714-33721.

8. Redaelli S, Piazza R et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 2009; 27(3):469-471.

9. Redaelli S, Boschelli F et al. Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib. Leukemia 2010; 24(6):1223-1227.

10. Melo JV, Chuah C. Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. Hematology Am Soc Hematol Educ Program 2008;427-435.

11. Messersmith WA, Rajeshkumar NV et al. Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts. Mol Cancer Ther 2009; 8(6):1484-1493.

12. Rabbani SA, Valentino ML et al. SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol Cancer Ther 2010; 9(5):1147-1157.

13. Saad F, Lipton A. SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat Rev 2010; 36(2):177-184.