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TOZASERTIB IN CLINICS FOR AURORA INHIBITION

by Selleckchem | Mar 13 2012

AURORA KINASE INHIBITION AND TOZASERTIB:

Three isoforms of the aurora kinase have been isolated in human tissue (A,B and C) which function on different aspects of the mitosis cycle. Aurora kinases are significant as targets for chemotherapeutic action since they are elevated in many different cancer types.[1;2] Small molecule inhibitors of aurora kinases, such as VX-680 [3] (Tozasertib), ZM447439 [4;5] and Hesperadin [6] have been developed and successfully trialed on several cancer groups including breast [7], colon [8], prostate [8;9] and in acute myeloid leukemia (AML) [10-14]. The initial results obtained for the Tozasertib Aurora kinase inhibitor [15;16] has lead to its advancement into phase 1 and phase 2 clinical trials.

VX-680 (MK-0457, Tozasertib) Chemical Structure

Tozasertib: Properties and Availability

Tozasertib is is available in high purity from a variety of Tozasertib suppliers. Tozasertib price varies greatly between suppliers ranging from $40 – 170 for a 25 mg vial, to buy Tozasertib researchers are advised to shop carefully to obtain the best value for money. For Tozasertib stability in solution it is recommended that all stocks be stored at -20°C and freeze/thaw cycles be kept to a minimum. Tozasertib solubility like so many similar compounds is poor in both aqueous and alcoholic solutions but will dissolve in DMSO up to 100 mg/ml.

Tozasertib IC50 is an effective inhibitor of all isoforms of Aurora kinases with values ranging between 0.6 – 18 nM, in addition Tozaertib has been demonstrated to inhibit ABL kinase (IC50 30 nM), a mutant variant of ABL kinase (T3151; IC50 42 nM) and FLT3 (30 nM). [17;18]

TOZASERTIB: Pre-Clinical investigation

Tozasertib is marketed originally by Vertex (Cambridge, MA) under the code VX-680 but was later renamed to MK-0457 by Merck (Whitehouse Station, NY). Preclinical investigations into Tozasertib established to be an inhibitor of all isoforms of Aurora kinases which suppressed tumor growth in a variety of xenographs. [15] To investigate Tozasertib in regard to overcoming chemotherapeutic resistance is was tested against mutant forms of BCR-ABL. KIT and EGFR. Results indicated activity for Tozasertib at IC50 concentrations of 200 nM in Imatinib and BMS-354825 resistant cell lines.[19] Subsequently Tozasertib was pre-clinical tested against Ewing’s sarcoma [20], colon [15], pancreatic [15] , Ovarian [21], oral squamous [22], nasopharyngeal carcinoma [23] and renal cell carcinoma [24] where mostly positive activities were discovered.

Tozasertib: Clinical status

Since Tozasertib has been demonstrated to be effective in mutated cell lines an phase 1 investigation in T3151 ABL – mutated patients with either chronic myeloid cancer (CML) or Philadelphia chromosome positive acute lymphocytic leukemia (ALL) was conducted. Of the three subjects tested at non toxic dosing levels all demonstrated a significant response, once higher doses were applied clinical responses were noted [25]. More recently a phase 1 trial in patients with advanced solid tumors established dose limiting toxicity at 96 mg/m²/h subsequently the MTD set to 64 mg/m²/h. Nearly 50% of the 27 patients achieved stable disease at the time of publication and further updates seem promising.[26]

References

1. Agnese V, Bazan V et al. The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 2007; 18 Suppl 6:vi47-vi52.

2. Doggrell SA. Dawn of Aurora kinase inhibitors as anticancer drugs. Expert Opin Investig Drugs 2004; 13(9):1199-1201.

3. Lavelle F. [The Aurora kinase inhibitor VX680, leader of a new family of antitumoral agents]. Bull Cancer 2004; 91(4):300-301.

4. Georgieva I, Koychev D et al. ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines. Neuroendocrinology 2010; 91(2):121-130.

5. Bebbington D, Binch H et al. The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg Med Chem Lett 2009; 19(13):3586-3592.

6. Hauf S, Cole RW et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 2003; 161(2):281-294.

7. Yang H, Ou CC et al. Aurora-A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res 2004; 64(2):463-467.

8. Azzariti A, Bocci G et al. Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer. Br J Cancer 2011; 104(5):769-780.

9. Lee EC, Frolov A et al. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 2006; 66(10):4996-5002.

10. Aihara A, Tanaka S et al. The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma. J Hepatol 2010; 52(1):63-71.

11. Lowenberg B, Muus P et al. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood 2011; 118(23):6030-6036.

12. Tao Y, Leteur C et al. The aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe. Cell Cycle 2009; 8(19):3172-3181.

13. Walsby E, Walsh V et al. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica 2008; 93(5):662-669.

14. Yang J, Ikezoe T et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007; 110(6):2034-2040.

15. Harrington EA, Bebbington D et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004; 10(3):262-267.

16. Lavelle F. [The Aurora kinase inhibitor VX680, leader of a new family of antitumoral agents]. Bull Cancer 2004; 91(4):300-301.

17. Akahane D, Tauchi T et al. Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL: in vitro and in vivo studies. Cancer Sci 2008; 99(6):1251-1257.

18. Cheetham GM, Charlton PA et al. Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680. Cancer Lett 2007; 251(2):323-329.

19. Carter TA, Wodicka LM et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 2005; 102(31):11011-11016.

20. Winter GE, Rix U et al. An integrated chemical biology approach identifies specific vulnerability of Ewing's sarcoma to combined inhibition of Aurora kinases A and B. Mol Cancer Ther 2011; 10(10):1846-1856.

21. Lin YG, Immaneni A et al. Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth. Clin Cancer Res 2008; 14(17):5437-5446.

22. Pan C, Yan M et al. Aurora kinase small molecule inhibitor destroys mitotic spindle, suppresses cell growth, and induces apoptosis in oral squamous cancer cells. Oral Oncol 2008; 44(7):639-645.

23. Wan XB, Long ZJ et al. Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells. Carcinogenesis 2008; 29(10):1930-1937.

24. Li Y, Zhang ZF et al. VX680/MK-0457, a potent and selective Aurora kinase inhibitor, targets both tumor and endothelial cells in clear cell renal cell carcinoma. Am J Transl Res 2010; 2(3):296-308.

25. Giles FJ, Cortes J et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007; 109(2):500-502.

26. Traynor AM, Hewitt M et al. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 2011; 67(2):305-314.