Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

Biochemical Pharmacology

Volumn 80, Issue 10, 2010, Pages 1507-1516

  Eriksson, Anna ^a   Höglund, Martin ^a   Lindhagen, Elin ^a   Åleskog, Anna ^a   Hassan, Sadia Bashir ^a   Ekholm, Carina ^b   Fhölenhag, Karin ^b   Jensen, Annika Jenmalm ^b   Löthgren, Agneta ^b   Scobie, Martin ^b   Larsson, Rolf ^b   Parrow, Vendela ^b,c  

^a UPPSALA UNIVERSITY   (Sweden)

^b BIOVITRUM AB   (Sweden)

^c Akinion Pharmaceuticals AB   (Sweden)

Author keywords

Acute myeloid leukemia; FLT3; New drug development; Tyrosine kinase inhibitor

Indexed keywords

AB 200434; AKN 032; FIBROBLAST GROWTH FACTOR RECEPTOR 3; PROTEIN TYROSINE KINASE INHIBITOR; SUNITINIB; UNCLASSIFIED DRUG; 2-AMINOPYRAZINE; ANTINEOPLASTIC AGENT; CD135 ANTIGEN; PYRAZINE DERIVATIVE;

ACUTE GRANULOCYTIC LEUKEMIA; ADULT; AGED; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER CELL CULTURE; CYTOTOXICITY; DRUG ACTIVITY; DRUG EFFECT; DRUG IDENTIFICATION; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CELL SURVIVAL; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG EFFECTS; DRUG SCREENING; ENZYMOLOGY; EPITHELIUM CELL; FLOW CYTOMETRY; LEUKEMIA, MYELOMONOCYTIC, ACUTE; MIDDLE AGED; PATHOLOGY; TUMOR CELL LINE; YOUNG ADULT;

ADULT; AGED; ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; CELL SURVIVAL; DOSE-RESPONSE RELATIONSHIP, DRUG; EPITHELIAL CELLS; FEMALE; FLOW CYTOMETRY; FMS-LIKE TYROSINE KINASE 3; HUMANS; LEUKEMIA, MYELOMONOCYTIC, ACUTE; MALE; MICE; MIDDLE AGED; MOLECULAR STRUCTURE; PYRAZINES; XENOGRAFT MODEL ANTITUMOR ASSAYS; YOUNG ADULT;

EID: 77957017186     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcp.2010.08.002     Document Type: Article

References (45)

1. Janne P.A., Gray N., Settleman J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 2009, 8:709-723.
2. Druker B.J., Talpaz M., Resta D.J., Peng B., Buchdunger E., Ford J.M., et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001, 344:1031-1037.
3. Fausel C. Targeted chronic myeloid leukemia therapy: seeking a cure. J Manag Care Pharm 2007, 13:8-12.
4. Knight Z.A., Lin H., Shokat K.M. Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 2010, 10:130-137.
5. Apsel B., Blair J.A., Gonzalez B., Nazif T.M., Feldman M.E., Aizenstein B., et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol 2008, 4:691-699.
6. Lowenberg B., Downing J.R., Burnett A. Acute myeloid leukemia. N Engl J Med 1999, 341:1051-1062.
7. Soverini S., Martinelli G., Iacobucci I., Baccarani M. Imatinib mesylate for the treatment of chronic myeloid leukemia. Expert Rev Anticancer Ther 2008, 8:853-864.
8. Scholl C., Gilliland D.G., Frohling S. Deregulation of signaling pathways in acute myeloid leukemia. Semin Oncol 2008, 35:336-345.
9. Ozeki K., Kiyoi H., Hirose Y., Iwai M., Ninomiya M., Kodera Y., et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 2004, 103:1901-1908.
10. Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br J Haematol 2007, 138:687-699.
11. Kottaridis P.D., Gale R.E., Frew M.E., Harrison G., Langabeer S.E., Belton A.A., et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001, 98:1752-1759.
12. Thiede C., Steudel C., Mohr B., Schaich M., Schakel U., Platzbecker U., et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002, 99:4326-4335.
13. Small D. FLT3 mutations: biology and treatment. Hematol Am Soc Hematol Educ Program 2006, 178-184.
14. Sanz M., Burnett A., Lo-Coco F., Lowenberg B. FLT3 inhibition as a targeted therapy for acute myeloid leukemia. Curr Opin Oncol 2009, 21:594-600.
15. Safaian N.N., Czibere A., Bruns I., Fenk R., Reinecke P., Dienst A., et al. Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res 2009, 33:348-350.
16. Fiedler W., Serve H., Dohner H., Schwittay M., Ottmann O.G., O'Farrell A.M., et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005, 105:986-993.
17. Patel HK, Milanov ZV, Mehta SA, Grotzfeld RM, Lai AG, Fabian MA, et al. Discovery of potent and specific FLT3 kinase inhibitors. Meeting abstract. Poster nr MEDI-123. San Diego, CA: American Chemical Society National Meeting; 2005.
18. Mathis G. HTRF(R) technology. J Biomol Screen 1999, 4:309-314.
19. Botling J., Liminga G., Larsson R., Nygren P., Nilsson K. Development of vincristine resistance and increased sensitivity to cyclosporin A and verapamil in the human U-937 lymphoma cell line without overexpression of the 170-kDa P-glycoprotein. Int J Cancer 1994, 58:269-274.
20. Levis M., Allebach J., Tse K.F., Zheng R., Baldwin B.R., Smith B.D., et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 2002, 99:3885-3891.
21. Lange B., Valtieri M., Santoli D., Caracciolo D., Mavilio F., Gemperlein I., et al. Growth factor requirements of childhood acute leukemia: establishment of GM-CSF-dependent cell lines. Blood 1987, 70:192-199.
22. Asou H., Tashiro S., Hamamoto K., Otsuji A., Kita K., Kamada N. Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991, 77:2031-2036.
23. Dalton W.T., Ahearn M.J., McCredie K.B., Freireich E.J., Stass S.A., Trujillo J.M. HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3. Blood 1988, 71:242-247.
24. Collins S.J., Gallo R.C., Gallagher R.E. Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature 1977, 270:347-349.
25. Shankar D.B., Li J., Tapang P., Owen McCall J., Pease L.J., Dai Y., et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood 2007, 109:3400-3408.
26. Larsson R., Kristensen J., Sandberg C., Nygren P. Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorometric microculture cytotoxicity assay (FMCA). Int J Cancer 1992, 50:177-185.
27. Smith P.K., Krohn R.I., Hermanson G.T., Mallia A.K., Gartner F.H., Provenzano M.D., et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985, 150:76-85.
28. Lindhagen E., Nygren P., Larsson R. The fluorometric microculture cytotoxicity assay. Nat Protoc 2008, 3:1364-1369.
29. Rickardson L., Fryknas M., Haglund C., Lovborg H., Nygren P., Gustafsson M.G., et al. Screening of an annotated compound library for drug activity in a resistant myeloma cell line. Cancer Chemother Pharmacol 2006, 58:749-758.
30. Lovborg H., Nygren P., Larsson R. Multiparametric evaluation of apoptosis: effects of standard cytotoxic agents and the cyanoguanidine CHS 828. Mol Cancer Ther 2004, 3:521-526.
31. Lindhagen E., Eriksson A., Wickstrom M., Danielsson K., Grundmark B., Henriksson R., et al. Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemia. Eur J Haematol 2008, 81:344-353.
32. Hollingshead M.G., Alley M.C., Camalier R.F., Abbott B.J., Mayo J.G., Malspeis L., et al. In vivo cultivation of tumor cells in hollow fibers. Life Sci 1995, 57:131-141.
33. Alley M.C., Scudiero D.A., Monks A., Hursey M.L., Czerwinski M.J., Fine D.L., et al. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 1988, 48:589-601.
34. Jonsson E., Friberg L.E., Karlsson M.O., Hassan S.B., Freijs A., Hansen K., et al. Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats. Cancer Chemother Pharmacol 2000, 46:493-500.
35. Marquardt D. An algorithm for least-squares estimation of nonlinear parameters. J Soc Ind Appl Math 1963, 11:431-441.
36. Chow L.Q., Eckhardt S.G. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007, 25:884-896.
37. Zarrinkar P.P., Gunawardane R.N., Cramer M.D., Gardner M.F., Brigham D., Belli B., et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009, 114:2984-2992.
38. Auclair D., Miller D., Yatsula V., Pickett W., Carter C., Chang Y., et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007, 21:439-445.
39. O'Farrell A.M., Abrams T.J., Yuen H.A., Ngai T.J., Louie S.G., Yee K.W., et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003, 101:3597-3605.
40. Quentmeier H., Reinhardt J., Zaborski M., Drexler H.G. FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 2003, 17:120-124.
41. Kennedy J.A., Barabe F. Investigating human leukemogenesis: from cell lines to in vivo models of human leukemia. Leukemia 2008, 22:2029-2040.
42. Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K., Vistica D., et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst 1991, 83:757-766.
43. Larsson R. Prediction of cytotoxic drug resistance in acute leukemia 1998, Marcel Dekker Inc., New York.
44. Nygren P., Fridborg H., Csoka K., Sundstrom C., de la Torre M., Kristensen J., et al. Detection of tumor-specific cytotoxic drug activity in vitro using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients. Int J Cancer 1994, 56:715-720.
45. Knapper S., Mills K.I., Gilkes A.F., Austin S.J., Walsh V., Burnett A.K. The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood 2006, 108:3494-3503.