A non-ATP-competitive dual inhibitor of JAK2V617F and BCR-ABLT315I kinases: Elucidation of a novel therapeutic spectrum based on substrate competitive inhibition

Genes and Cancer

Volumn 1, Issue 4, 2010, Pages 331-345

  Jatiani, Shashidhar S ^a,d   Cosenza, Stephen C ^a,d   Ramana Reddy, M V ^a,d   Ha, Ji Hee ^a,e   Baker, Stacey J ^a,d   Samanta, Ajoy K ^b   Olnes, Matthew J ^c   Pfannes, Loretta ^c   Sloand, Elaine M ^c   Arlinghaus, Ralph B ^b   Premkumar Reddy, E ^a,e  

^a TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

^d MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER   (United States)

Author keywords

BCR ABL; CML; CMPD; JAK2; MDS

Indexed keywords

ALPHA BENZOYLSTYRYLBENZYLSULFIDE; ANTINEOPLASTIC AGENT; BCR ABL PROTEIN; INTERLEUKIN 3; JANUS KINASE 2; ON 044580; PROTEIN TYROSINE KINASE INHIBITOR; STAT5 PROTEIN; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CANCER RESISTANCE; CELL PROLIFERATION; CHRONIC MYELOID LEUKEMIA; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOGENETICS; CYTOTOXICITY; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; ENZYME SPECIFICITY; HUMAN; HUMAN CELL; IC 50; MONOSOMY 7; MYELODYSPLASTIC SYNDROME; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; WILD TYPE;

EID: 79952037687     PISSN: 19476019     EISSN: 19476027     Source Type: Journal    
DOI: 10.1177/1947601910371337     Document Type: Article

References (75)

1. Rane SG, Reddy EP. JAKs, STATs and Src kinases in hematopoiesis. Oncogene. 2002;21:3334-58.
2. O'Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 2002;109:S121-31.
3. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93:385-95.
4. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, et al. Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J. 1998;17:5321-33.
5. Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffé M, et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science. 1997;278:1309-12.
6. Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, et al. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptorassociated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood. 1997;90:2535-40.
7. Aringer M, Cheng A, Nelson JW, Chen M, Sudarshan C, Zhou YJ, et al. Janus kinases and their role in growth and disease. Life Sci. 1999;64:2173-86.
8. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res. 2005;65:2662-7.
9. Griesinger F, Hennig H, Hillmer F, Podleschny M, Steffens R, Pies A, et al. A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia. Genes Chromosomes Cancer. 2005;44:329-33.
10. Cirmena G, Aliano S, Fugazza G, Bruzzone R, Garuti A, Bocciardi R, et al. A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11) in a patient with acute myeloid leukemia. Cancer Genet Cytogenet. 2008;183:105-8.
11. Murati A, Gelsi-Boyer V, Adélaïde J, Perot C, Talmant P, Giraudier S, et al. PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Leukemia. 2005;19:1692-6.
12. Mark HF, Sotomayor EA, Nelson M, Chaves F, Sanger WG, Kaleem Z, et al. Chronic idiopathic myelofibrosis (CIMF) resulting from a unique 3;9 translocation disrupting the janus kinase 2 (JAK2) gene. Exp Mol Pathol. 2006;81:217-23.
13. Najfeld V, Cozza A, Berkofsy-Fessler W, Prchal J, Scalise A. Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasms. Exp Hematol. 2007;35:1668-76.
14. Poitras JL, Dal Cin P, Aster JC, Deangelo DJ, Morton CC. Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. Genes Chromosomes Cancer. 2008;47:884-9.
15. Nebral K, Denk D, Attarbaschi A, König M, Mann G, Haas OA, et al. Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia. 2009;23:134-43.
16. Joos S, Küpper M, Ohl S, von Bonin F, Mechtersheimer G, Bentz M, et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res. 2000;60:549-52.
17. Shannon K, Van Etten RA. JAKing up hematopoietic proliferation. Cancer Cell. 2005;7:291-3.
18. Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood. 2006;108: 2173-81.
19. Ma W, Kantarjian H, Zhang X, Yeh CH, Zhang ZJ, Verstovsek S, et al. Mutation profile of JAK2 transcripts in patients with chronic myeloproliferative neoplasias. J Mol Diagn. 2009;11:49-53.
20. Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet. 2008;372:1484-92.
21. Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M, et al. Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood. 2009;113:646-8.
22. Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;106:9414-8.
23. Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol. 2009;144:930-2.
24. Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, et al. JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia. Leukemia. 2005;19:1843-4.
25. Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood. 2005;106:3370-3.
26. Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood. 2005;106:3377-9.
27. Lee JW, Kim YG, Soung YH, Han KJ, Kim SY, Rhim HS, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene. 2006;25:1434-6.
28. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-61.
29. James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature. 2005;434:1144-8.
30. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-90.
31. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-97.
32. Hellström-Lindberg E, Cazzola M. The role of JAK2 mutations in RARS and other MDS. Hematol Am Soc Hematol Educ Program. 2008:52-9.
33. Remacha AF, Nomdedéu JF, Puget G, Estivill C, Sarda MP, Canals C, et al. Occurrence of the JAK2 V617F mutation in the WHO provisional entity: myelodysplastic/myeloproliferative disease, unclassifiablerefractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica. 2006;91:719-20.
34. Lee TS, Ma W, Zhang X, Giles F, Kantarjian H, Albitar M. Mechanisms of constitutive activation of Janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations. Cancer. 2009;115:1692-700.
35. Lu X, Huang LJ, Lodish HF. Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J Biol Chem. 2008;283:5258-66.
36. Zhao L, Ma Y, Seemann J, Huang LJ. A regulating role of JAK2 FERM domain in hyperactivation of JAK2(V617F). Biochem J. 2010;426:91-8.
37. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459-68.
38. Chen G, Zeng W, Miyazato A, Billings E, Maciejewski JP, Kajigaya S, et al. Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. Blood. 2004;104:4210-8.
39. Sloand EM, Yong AS, Ramkissoon S, Solomou E, Bruno TC, Kim S, et al. Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor. Proc Natl Acad Sci U S A 2006;103:14483-8.
40. Haase D, Germing U, Schanz J, Pfeilstöcker M, Nöslinger T, Hildebrandt B, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110:4385-95.
41. Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289:1130-1135.
42. Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99:3129-3135.
43. Haase D. Cytogenetic features in myelodysplastic syndromes. Ann Hematol. 2008;87:515-26.
44. Touw IP, Dong F. Severe congenital neutropenia terminating in acute myeloid leukemia: disease progression associated with mutations in the granulocyte-colony stimulating factor receptor gene. Leuk Res. 1996;20:629-631.
45. Hexner EO, Serdikoff C, Jan M, Swider CR, Robinson C, Yang S, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/ STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008;111:5663-71.
46. Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia. 2008;22:1790-2.
47. Mesa RA, Tefferi A. Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. Expert Opin Emerg Drugs. 2009;14(3):471-9.
48. Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009;23:1441-5.
49. Mathur A, Mo JR, Kraus M, O'Hare E, Sinclair P, Young J, et al. An inhibitor of Janus kinase 2 prevents polycythemia in mice. Biochem Pharmacol. 2009;78:382-9.
50. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-6.
51. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401.
52. Blum G, Gazit A, Levitzki A. Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry. 2000;39:15705-12.
53. Reddy MV, Pallela VR, Cosenza SC, Mallireddigari MR, Patti R, Bonagura M, et al. Design, synthesis and evaluation of (E)-alpha-benzylthio chalcones as novel inhibitors of BCR-ABL kinase. Bioorg Med Chem. 2010;18:2317-26.
54. Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 1996;379:645-8.
55. Pedranzini L, Dechow T, Berishaj M, Comenzo R, Zhou P, Azare J, et al. Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res. 2006;66:9714-21.
56. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994;371:346-7.
57. Adrián FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol. 2006;2:95-102.
58. Samanta AK, Chakraborty SN, Wang Y, Kantarjian H, Sun X, Hood J, et al. Jak2 inhibition deactivates Lyn kinase through the SET-PP2ASHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients. Oncogene. 2009;28:1669-81.
59. Delhommeau F, Pisani DF, James C, Casadevall N, Constantinescu S, Vainchenker W. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci. 2006;63:2939-53.
60. Tefferi A, Gilliland DG. Oncogenes in myeloproliferative disorders. Cell Cycle. 2007;6:550-66.
61. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105:2640-53.
62. Mian AA, Schüll M, Zhao Z, Oancea C, Hundertmark A, Beissert T, et al. The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL. Leukemia. 2009;23:1614-21.
63. Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001;20:6188-95.
64. Xie S, Lin H, Sun T, Arlinghaus RB. Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene. 2002;21:7137-46.
65. Samanta AK, Lin H, Sun T, Kantarjian H, Arlinghaus RB. Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res. 2006;66:6468-72.
66. Ferrajoli A, Faderl S, Van Q, Koch P, Harris D, Liu Z, et al. WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells. Cancer Res. 2007;67:11291-9.
67. Jallades L, Hayette S, Tigaud I, Johnston A, Coiffier B, Magaud J-P, et al. Emergence of therapy-unrelated CML on a background of BCRABL-negative JAK2 V617F-positive chronic idiopathic myelofibrosis. Leuk Res. 2008;32:1608-10.
68. Krämer A, Reiter A, Kruth J, Erben P, Hochhaus A, Müller M, et al. JAK2-V617F mutation in a patient with Philadelphia-chromosomepositive chronic myeloid leukaemia. Lancet Oncol. 2007;8:658-60.
69. Inami M, Inokuchi K, Okabe M, Kosaka F, Mitamura Y, Yamaguchi H, et al. Polycythemia associated with the JAK2V617F mutation emerged during treatment of chronic myelogenous leukemia. Leukemia. 2007;21:1103-4.
70. Hussein K, Bock O, Seegers A, Flasshove M, Henneke F, Buesche G, et al. Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABLtranslocation and JAK2V617F mutation. Blood. 2007;109:4106-7.
71. Krämer A. JAK2-V617F and BCR-ABL-double jeopardy? Leuk Res. 2008;32:1489-90.
72. Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001;20:6188-95.
73. Wilson-Rawls J, Liu J, Laneuville P, Arlinghaus RB. P210 Bcr-Abl interacts with the interleukin-3 beta c subunit and constitutively activates Jak2. Leukemia. 1997;Suppl 3:428-31.
74. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005;8:355-68.
75. Sloand EM, Kim S, Fuhrer M, Risitano AM, Nakamura R, Maciejewski JP, et al. Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. Blood. 2002;100:4427-32.