Cancer II pp 1-37 | Cite as

Progress in the Discovery of BCR-ABL Kinase Inhibitors for the Treatment of Leukemia

  • Paul W. ManleyEmail author
  • Nikolaus J. Stiefl
Part of the Topics in Medicinal Chemistry book series (TMC, volume 28)


Chemists first employed structure–activity relationships in designing busulphan, a chemotherapeutic for chronic myeloid leukemia (CML) in the 1950s. However, despite chemotherapy and later interferon immunotherapy, the median survival of patients remained less than 5 years. The elucidation that CML is driven by a tyrosine kinase mutation in haematopoietic stem cells enabled the discovery of imatinib, the first oncoprotein-targeted drug. Imatinib revolutionised CML therapy and set a new paradigm for the discovery of improved cancer drugs. Subsequently, medicinal chemists have capitalised upon X-ray co-crystal structures to rationally design superior ATP-competitive and allosteric ABL inhibitors. This progress has translated into clinical practice, such that chronic phase CML patients treated according to current guidelines have a normal life expectancy and many might in the future be able to discontinue treatment and maintain treatment-free remission. This review documents the history of CML drug discovery from arsenic through to asciminib, and progress towards a potential leukemia cure.


Abelson tyrosine kinase (BCR-ABL) Allosteric inhibitor Chronic myeloid leukemia (CML) Kinase inhibitor design Leukemia molecular response Targeted cancer drug 


  1. 1.
    Manley PW, Holzer P, Möbitz H, Skaanderup PR, Stauffer F (2015) Progress into the era of genomically targeted cancer drugs: 50 years of anticancer medicinal chemistry. Med Chem Rev 50:185–203Google Scholar
  2. 2.
    Neumann E (1872) Ein neuer Fall von Leukamie mit Erkrankung des Knochenmarks. Archives Heilkunde 13:502–508Google Scholar
  3. 3.
    Höglund M, Sandin F, Simonsson B (2015) Epidemiology of chronic myeloid leukaemia: an update. Ann Hematol 94(Suppl 2):241–247Google Scholar
  4. 4.
    Nowell PC (2007) Discovery of the Philadelphia chromosome: a personal perspective. J Clin Invest 117:2033–2035PubMedPubMedCentralGoogle Scholar
  5. 5.
    Hunter T (2007) Treatment for chronic myelogenous leukemia: the long road to imatinib. J Clin Invest 117:2036–2043PubMedPubMedCentralGoogle Scholar
  6. 6.
    Rowley JD (1973) A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–293PubMedGoogle Scholar
  7. 7.
    Byrne M, Wray J, Reinert B, Wu Y, Nickoloff J, Lee S-H, Hromas R, Williamson E (2014) Mechanisms of oncogenic chromosomal translocations. Ann N Y Acad Sci 1310:89–97PubMedGoogle Scholar
  8. 8.
    Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM (1999) The biology of chronic myeloid leukemia. New Engl J Med 341:164–172PubMedGoogle Scholar
  9. 9.
    Griffin JD (1986) Management of chronic myelogenous leukemia. Semin Hematol 23(3 Suppl 1):20–26PubMedGoogle Scholar
  10. 10.
    Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, Sawyers C, Shah N, Stock W, Willman CL, Friend S, Linsley PS (1986) Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 103:2794–2799Google Scholar
  11. 11.
    Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilot F, Horowitz M, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R, Hehlman R (2006) Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108:1809–1820PubMedGoogle Scholar
  12. 12.
    Mahon F-X, Etienne G (2014) Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res 20:310–322PubMedGoogle Scholar
  13. 13.
    Press RD (2010) Major molecular response in CML patients treated with tyrosine kinase inhibitors: the paradigm for monitoring targeted cancer therapy. Oncologist 15:744–749PubMedPubMedCentralGoogle Scholar
  14. 14.
    Cross NCP, Hochhaus A, Müller MC (2015) Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization. Ann Hematol 94(Suppl 2):219–225Google Scholar
  15. 15.
    Kampen KR (2012) The discovery and early understanding of leukemia. Leuk Res 36:6–13PubMedGoogle Scholar
  16. 16.
    Geary CG (2000) The story of chronic myeloid leukaemia. Br J Haematol 110:2–11PubMedGoogle Scholar
  17. 17.
    Piller GJ (2001) Leukaemia – a brief historical review from ancient times to 1950. Br J Haematol 112:282–292PubMedGoogle Scholar
  18. 18.
    Lissauer D (1865) Zwei Fälle von Leucaemie. Berl Klin Wochenschr 2:403–404Google Scholar
  19. 19.
    Senn N (1903) Case of splenomedullary leukemia successfully treated by the use of Roentgen rays. Med Rec 64:281–282Google Scholar
  20. 20.
    Paulino AC, Reddy SP (1996) Splenic irradiation in the palliation of patients with lymphoproliferative and myeloproliferative disorders. Am J Hosp Palliat Care 13(6):32–35PubMedGoogle Scholar
  21. 21.
    Osgood EE, Seaman AJ, Tivey H (1955) Comparative survival times of x-ray treated versus P32 treated patients with chronic leukemias under the program of titrated, regularly spaced total-body irradiation. Radiology 64:373–381PubMedGoogle Scholar
  22. 22.
    Galton DAG (1956) Use of myleran and similar agents in chronic leukemias. Adv Cancer Res 4:73–112PubMedGoogle Scholar
  23. 23.
    Lawrence JH, Dobson RL, Low-Beer BVA, Brown BR (1948) Chronic myelogenous leukemia: a study of one hundred and twenty-nine cases treated with radioactive phosphorus. JAMA 136:672–677Google Scholar
  24. 24.
    Papac RJ (2001) Origins of cancer therapy. Yale J Biol Med 74:391–398PubMedPubMedCentralGoogle Scholar
  25. 25.
    Avendano C, Menendez JC (2008) DNA alkylating agents. In: Medicinal chemistry of anticancer drugs. Elsevier, Amsterdam, pp 139–176Google Scholar
  26. 26.
    Haddow A, Timmis GM (1953) Myleran in chronic myeloid leukemia. Chemical constitution and biological action. Lancet:207–208Google Scholar
  27. 27.
    Galton DAG (1953) Myleran in chronic myeloid leukaemia: results of treatment. Lancet:208–213Google Scholar
  28. 28.
    Medical Research Council’s Working Party for Therapeutic Trials in Leukaemia (1968) Chronic granulocytic leukaemia: comparison of radiotherapy and busulphan therapy. Br Med J 1(5586):201–208Google Scholar
  29. 29.
    Galaup A, Paci A (2013) Pharmacology of dimethane sulfonate alkylating agents: busulfan and treosulfan. Expert Opin Drug Metab Toxicol 9:333–347PubMedGoogle Scholar
  30. 30.
    Probin V, Wang Y, Zhou D (2007) Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway. Free Radic Biol Med 42:1858–1865PubMedPubMedCentralGoogle Scholar
  31. 31.
    Dresler WFC, Stein R (1869) Ueber den Hydroxylharnstoff. Justus Liebigs Ann Chem 150:242–252Google Scholar
  32. 32.
    Stearns B, Losee KL, Bernstein J (1963) Hydroxyurea: a new type of potential antitumor agent. J Med Chem 6:201PubMedGoogle Scholar
  33. 33.
    Kennedy BJ, Yarbro JW (1966) Metabolic and therapeutic effects of hydroxyurea in chronic myeloid leukemia. JAMA 195:1038–1043PubMedGoogle Scholar
  34. 34.
    Stevens MR (1999) Hydroxyurea: an overview. J Biol Regul Homeost Agents 13:172–175PubMedGoogle Scholar
  35. 35.
    Alvino GM, Collingwood D, Murphy JM, Delrow J, Brewer BJ, Raghuraman MK (2007) Replication in hydroxyurea: it’s matter of time. Mol Cell Biol 27:6396–6406PubMedPubMedCentralGoogle Scholar
  36. 36.
    Koc A, Wheeler LJ, Mathews CK, Merrill GF (2004) Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J Biol Chem 279:223–230PubMedGoogle Scholar
  37. 37.
    Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queisser W, Loffler H, Heinze B, Georgii A (1993) Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood 82:398–407PubMedGoogle Scholar
  38. 38.
    Hehlmann R (1988) Cytostatic therapy of chronic myelogenous leukemia: review and perspectives. In: Huhn D, Hellriegel KP, Niederle N (eds) Chronic myelocytic leukemia and interferon. Springer, Berlin, pp 102–112Google Scholar
  39. 39.
    Gonzalez-Navajas JM, Lee J, David M, Raz E (2012) Immunomodulatory functions of type I interferons. Nat Rev Immunol 12:125–135PubMedPubMedCentralGoogle Scholar
  40. 40.
    Talpaz M, Mercer J, Hehlmann R (2015) The interferon-alpha revival in CML. Ann Hematol 94(Suppl 2):S195–S207PubMedGoogle Scholar
  41. 41.
    Talpaz M, McCredie KB, Mavligit GM, Gutterman JU (1983) Leukocyte interferon-induced myeloid cytoreduction in chronic myelogenous leukemia. Blood 62:689–692PubMedGoogle Scholar
  42. 42.
    Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, Tura S (1999) An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood 94:1517–1536PubMedGoogle Scholar
  43. 43.
    Baccarani M, Rosti G, De Vivo A, Bonifazi F, Russo D, Martinelli G, Testoni N, Amabile M, Fiacchini M, Montefusco E et al (2002) A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood 99:1527–1535PubMedGoogle Scholar
  44. 44.
    Wang Y, Youngster S, Grace M, Bausch J, Bordens R, Wyss DF (2002) Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drug Deliv Rev 54:547–570PubMedGoogle Scholar
  45. 45.
    Dhalluin C, Ross A, Leuthold L, Foser S, Gsell B, Mueller F, Senn H (2005) Structural and biophysical characterization of the 40 kDa PEG-interferon-α2a and its individual positional isomers. Bioconjug Chem 16:504–517PubMedGoogle Scholar
  46. 46.
    Lipton JH, Khoroshko N, Golenkov A, Abdulkadyrov K, Nair K, Raghunadharao D, Brummendorf T, Yoo K, Bergstrom B (2007) Phase II, randomized, multicenter, comparative study of peginterferon-α-2a (40 kD) (Pegasys) versus interferon α-2a (Roferon-A) in patients with treatment-naive, chronic-phase chronic myelogenous leukemia. Leuk Lymphoma 48:497–505PubMedGoogle Scholar
  47. 47.
    European Association for the Study of the Liver (2015) EASL recommendations on treatment of hepatitis C 2015. J Hepatol 63:199–236Google Scholar
  48. 48.
    Hanks SK (2003) Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. Genome Biol 4:111PubMedPubMedCentralGoogle Scholar
  49. 49.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934PubMedGoogle Scholar
  50. 50.
    Meyer T, Regenass U, Fabbro D, Alteri E, Rosel J, Muller M, Caravatti G, Matter A (1989) A derivative of staurosporine (CGP41251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer 43:851–856PubMedGoogle Scholar
  51. 51.
    Morita Y, Takaishi T, Honda Z, Miyamoto T (1988) Role of protein kinase C in histamine release from human basophils. Allergy 43:100–104PubMedGoogle Scholar
  52. 52.
    Torley LW, Johnson BB, Dusza J (1987) Preparation of 4,5,6-substituted 2-pyrimidinamines as allergy inhibitors, antiasthmatics, and hypoglycemics. Eur Patent Appl 233461, 26 Aug 1987Google Scholar
  53. 53.
    Paul R, Hallett WA, Hanifin JW, Reich MF, Johnson BD, Lenhard RH, Dusza JP, Kerwar SS, Lin Y, Pickett WC, Seifert CM, Torley LW, Tarrant ME, Wrenn S (1993) Preparation of substituted N-phenyl-4-aryl-2-pyrimidinamines as mediator release inhibitors. J Med Chem 36:2716–2725PubMedGoogle Scholar
  54. 54.
    Zimmermann J, Caravatti G, Mett H, Meyer T, Mueller M, Lydon NB, Fabbro D (1996) Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC). Arch Pharm 329:371–376Google Scholar
  55. 55.
    Geissler JF, Roesel JL, Meyer T, Trinks UP, Traxler P, Lydon NB (1992) Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. Cancer Res 52:4492–4498PubMedGoogle Scholar
  56. 56.
    Zimmermann J (1993) Preparation of 2-anilinopyrimidines as antiatherosclerotics and neoplasm inhibitors. Eur Patent Appl 564409, 6 Oct 1993Google Scholar
  57. 57.
    Zimmermann J, Buchdunger E, Mett H, Meyer T, Lydon NB, Traxler P (1996) (Phenylamino)pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg Med Chem Lett 6:1221–1226Google Scholar
  58. 58.
    Zimmermann J, Buchdunger E, Mett H, Meyer T, Lydon NB (1997) Potent and selective inhibitors of the ABL-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett 7:187–192Google Scholar
  59. 59.
    Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56:100–104PubMedGoogle Scholar
  60. 60.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566PubMedGoogle Scholar
  61. 61.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Sawyers CL (1999) Clinical efficacy and safety of an ABL specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia. Blood 94:368aGoogle Scholar
  62. 62.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedGoogle Scholar
  63. 63.
    Roy L, Guilhot J, Krahnke T, Guerci-Bresler A, Druker BJ, Larson RA, O’Brien S, So C, Massimini G, Guilhot F (2006) Survival advantage from imatinib compared with the combination interferon plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 108:1478–1484PubMedGoogle Scholar
  64. 64.
    Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23:1054–1061PubMedGoogle Scholar
  65. 65.
    Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358–364PubMedGoogle Scholar
  66. 66.
    Tong M, Seeliger MA (2014) Targeting conformational plasticity of protein kinases. ACS Chem Biol 10:190–200PubMedGoogle Scholar
  67. 67.
    Kornevc AP, Taylor SS (2015) Dynamics-driven allostery in protein kinases. Trends Biochem Sci 40:628–647Google Scholar
  68. 68.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289(5486):1938–1942PubMedGoogle Scholar
  69. 69.
    Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 62:4236–4243PubMedGoogle Scholar
  70. 70.
    Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, Kuriyan J (2003) Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112:859–871PubMedGoogle Scholar
  71. 71.
    Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW (2007) Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukemia. Acta Crystallogr 63:80–93Google Scholar
  72. 72.
    Tokarski JS, Newitt JA, Chang CYJ, Cheng JD, Wittekind M, Kiefer SE, Kish K, Lee FY, Borzillerri R, Lombardo LJ, Xie D, Zhang Y, Klei HE (2006) The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 66:5790–5797PubMedGoogle Scholar
  73. 73.
    Cowan-Jacob SW, Guez V, Fendrich G, Griffin JD, Fabbro F, Furet P, Liebetanz J, Mestan J, Manley PW (2004) Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem 4:285–299PubMedGoogle Scholar
  74. 74.
    Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau M, Reader V, Sweetman G, Bauer A, Bouwmeester T, Hopf C, Kruse U, Neubauer G, Ramsden N, Rick J, Kuster B, Drewes G (2007) Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 25:1035–1044PubMedGoogle Scholar
  75. 75.
    Karaman MW, Herrgard S, Treiber DK, Gallant P, Corey E, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132PubMedGoogle Scholar
  76. 76.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedGoogle Scholar
  77. 77.
    Hochhaus A, La Rosee P (2004) Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18:1321–1331PubMedGoogle Scholar
  78. 78.
    Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880PubMedGoogle Scholar
  79. 79.
    Apperley JF (2007) Part I: mechanisms of resistance to imatinib in chronic myeloid leukemia. Lancet Oncol 8:1018–1029PubMedGoogle Scholar
  80. 80.
    Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111(8):4022–4028PubMedGoogle Scholar
  81. 81.
    Manley PW, Blasco F, Mestan J, Aichholz A (2013) The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588. Bioorg Med Chem 21:3231–3239PubMedGoogle Scholar
  82. 82.
    Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M, Wiesmann M, Woodman R, Gallagher N (2010) Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg Med Chem 18:6977–6986PubMedGoogle Scholar
  83. 83.
    Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6:587–595PubMedGoogle Scholar
  84. 84.
    Das J, Barrish JC (2010) Dasatinib, a kinase inhibitor to treat chronic myelogenous leukemia. In: Analogue-based drug discovery II, pp 493–506Google Scholar
  85. 85.
    Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV, Shen Z, Cook LS, Doweyko AM, Pitt S, Pang S, Shen DR, Fang Q, de Fex HF, McIntyre KW, Shuster DJ, Gillooly KM, Behnia K, Schieven GL, Wityak J, Barrish JC (2006) 2-Aminothiazole as a novel kinase inhibitor template. Structure–activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-1, 3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem 49:6819–6832PubMedGoogle Scholar
  86. 86.
    Das J, Padmanabha R, Chen P, Norris DJ, Doweyko AMP, Barrish JC, Wityak J (2000) Preparation of cyclic protein tyrosine kinase inhibitors. PCT Int Appl 2000062778, 26 Oct 2000Google Scholar
  87. 87.
    Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LAM, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM (2004) Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658–6661PubMedGoogle Scholar
  88. 88.
    Vajpai N, Strauss A, Fendrich G, Cowan-Jacob SW, Manley PW, Grzesiek S, Jahnke W (2008) Solution conformations and dynamics of ABL kinase inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J Biol Chem 283:18292–18302PubMedGoogle Scholar
  89. 89.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401PubMedGoogle Scholar
  90. 90.
    O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MWN, Brian J, Druker BJ (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500–4505PubMedGoogle Scholar
  91. 91.
    Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531–2541PubMedGoogle Scholar
  92. 92.
    Aguilera DG, Tsimberidou AM (2009) Dasatinib in chronic myeloid leukemia: a review. Ther Clin Risk Manag 5:281–289PubMedPubMedCentralGoogle Scholar
  93. 93.
    Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, Corm S, Shah NP, Cervantes F, Silver RT, Niederwieser D, Stone RM, Dombret H, Larson RA, Roy L, Hughes T, Müller MC, Ezzeddine E, Countouriotis AM, Kantarjian HM (2008) Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22:1200–1206PubMedGoogle Scholar
  94. 94.
    Guilhot F, Apperley J, Kim DW, Eduardo O, Bullorsky EO, Michele Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, Heim D, Larson RA, Branford S, Muller MC, Agarwal P, Gollerkeri A, Talpaz M (2007) Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109:4143–4150PubMedGoogle Scholar
  95. 95.
    Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Soledad Undurraga M, Wang J, Kassack IJJ, Kim D-W, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Bradley-Garelik M, Zhu C, Hochhaus A (2012) Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 19:1123–1129Google Scholar
  96. 96.
    Shah NP, Guilot F, Cortes JE, Schiffer CA, Le Coutre P, Brummendorf TH, Kantarjian HM, Hochhaus A, Rousselot P, Mohamed H, Healey D, Cunningham M, Saglio G (2014) Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 123:2317–2324PubMedPubMedCentralGoogle Scholar
  97. 97.
    Parker WT, Ho M, Scott HS, Hughes TP, Branford S (2012) Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile. Blood 119:2234–2238PubMedGoogle Scholar
  98. 98.
    Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MWN, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone S, Tura S, Mahon F-X, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937PubMedGoogle Scholar
  99. 99.
    Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Furet P, Mestan J, Meyer T (2004) Urea-derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases. Bioorg Med Chem Lett 14:5793–5797PubMedGoogle Scholar
  100. 100.
    Eck MJ, Manley PW (2009) The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Curr Opin Cell Biol 21:288–295PubMedGoogle Scholar
  101. 101.
    Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D (2010) Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 1804:445–453PubMedGoogle Scholar
  102. 102.
    Weisberg E, Manley PW, Breitenstein W, Brueggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Mohammed A, Neuberg D, Wright RD, Gilliland DG, Griffin JD (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141PubMedGoogle Scholar
  103. 103.
    Jensen MR, Brüggen J, DiLea C, Mestan J, Manley PW (2006) AMN107: efficacy of the selective Bcr-Abl tyrosine kinase inhibitor in a murine model of chronic myelogenous leukemia. In: Abstracts of the 97th annual meeting of the American Association for Cancer Research, Washington, DC, 1-5 April 2006. Proc Am Assoc Cancer Res 47:61–62. Abstr 780Google Scholar
  104. 104.
    Manley PW, Zimmermann J (2012) Drug research leading to imatinib and beyond to nilotinib. In: Peters J-U (ed) Polypharmacology in drug discovery. Wiley, Hoboken, NJ, pp 409–421Google Scholar
  105. 105.
    Pierce AC, Sandretto KL, Guy W, Bemis GW (2002) Kinase inhibitors and the case for CH...O hydrogen bonds in protein–ligand binding. Proteins 49:567–576PubMedGoogle Scholar
  106. 106.
    Olsen JA, Banner DW, Seiler P, Wagner B, Tschopp T, Obst-Sander U, Kansy M, Müller K, Diederich F (2004) Fluorine interactions at the thrombin active site: protein backbone fragments H-Cα-C=O comprise a favourable C-F environment and interactions of C-F with electrophiles. ChemBioChem 5:666–675PubMedGoogle Scholar
  107. 107.
    Manley PW, Cowan-Jacob SW, Fendrich G, Jahnke W, Fabbro D (2011) Nilotinib, in comparison to both dasatinib and imatinib, possesses a greatly prolonged residence time when bound to the BCR-ABL kinase SH1 domain. In: Abstracts of the 53rd annual meeting of the American Society of Hematology, San Diego, CA, 10-13 Dec 2011. Blood 118(21):727. Abstr 1694Google Scholar
  108. 108.
    Weisberg E, Manley PW, Mestan J, Cowan-Jacob S, Ray A, Griffin JD (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94:1765–1769PubMedPubMedCentralGoogle Scholar
  109. 109.
    Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–2551PubMedGoogle Scholar
  110. 110.
    Tanaka C, Yin OQP, Sethuraman V, Smith T, Wang X, Grouss K, Kantarjian H, Giles F, Ottmann OG, Galitz L, Schran H (2009) Clinical pharmacokinetics of the BCR–ABL tyrosine kinase inhibitor nilotinib. Clin Pharmacol Ther 87:197–203PubMedGoogle Scholar
  111. 111.
    Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O’Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110:3540–3546PubMedGoogle Scholar
  112. 112.
    Le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, O’Brien SG, Kuliczkowski K, Hochhaus A, Mahon FX, Saglio G, Gobbi M, Kwong YL, Baccarani M, Hughes T, Martinelli G, Radich JP, Zheng M, Shou Y, Kantarjian H (2008) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111:1834–1839PubMedGoogle Scholar
  113. 113.
    Hochhaus A, Rosti G, Cross NCP, Steegmann JL, le Coutre P, Ossenkoppele G, Petrov L, Masszi T, Hellmann A, Griskevicius L, Wiktor-Jedrzejczak W, Rea D, Coriu D, Brümmendorf TH, Porkka K, Saglio G, Gastl G, Müller MC, Schuld P, Di Matteo P, Pellegrino A, Dezzani L, Mahon F-X, Baccarani M, Giles FJ (2015) Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia 30:57–64PubMedPubMedCentralGoogle Scholar
  114. 114.
    Hunter T, Sefton BM (1980) Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci U S A 77:1311–1315PubMedPubMedCentralGoogle Scholar
  115. 115.
    Myers MR, Setzer NN, Spada AP, Zulli AL, Hsu CYJ, Zilberstein A, Johnson SE, Hook LE, Jacoski MV (1997) The preparation and SAR of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: inhibitors of p56lck and EGF-R tyrosine kinase activity. Bioorg Med Chem Lett 7:417–420Google Scholar
  116. 116.
    Wang YD, Miller K, Boschelli DH, Ye F, Wu B, Floyd MB, Powell DW, Wissner A, Weber JM, Boschelli F (2000) Inhibitors of Src tyrosine kinase: the preparation and structure-activity relationship of 4-anilino-3-cyanoquinolines and 4-anilinoquinazolines. Bioorg Med Chem Lett 10:2477–2480PubMedGoogle Scholar
  117. 117.
    Boschelli DH (2002) 4-Anilino-3-quinolinecarbonitriles: an emerging class of kinase inhibitors. Curr Top Med Chem 2:1051–1063PubMedGoogle Scholar
  118. 118.
    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 (2001) Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 44:3965–3977PubMedGoogle Scholar
  119. 119.
    Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, Frost P, Ye F, Boschelli DH, Boschelli F (2003) 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 63:375–381PubMedGoogle Scholar
  120. 120.
    Boschelli F, Arndt K, Gambacorti-Passerini C (2010) Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer 46:1781–1789PubMedGoogle Scholar
  121. 121.
    Levinson NM, Boxer SG (2012) Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain. PLoS One 7(4):e29828PubMedPubMedCentralGoogle Scholar
  122. 122.
    Rix LLR, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G (2009) Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia 23:477–485PubMedGoogle Scholar
  123. 123.
    Vi Doan AW, Prescott H (2015) Bosutinib for the treatment of chronic myeloid leukemia. Am J Health Syst Pharm 72:439–447PubMedGoogle Scholar
  124. 124.
    Bruemmendorf TH, Cortes JE, Antonio de Souza C, Guilhot F, Duvillie L, Pavlov D, Gogat K, Countouriotis AM, Gambacorti-Passerini C (2015) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol 168:69–81Google Scholar
  125. 125.
    Huang WS, Zhu X, Wang Y, Azam M, Wen D, Sundaramoorthi R, Thomas RM, Liu S, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Daley GD, Iuliucci J, Dalgarno DC, Clackson T, Sawyer TK, Shakespeare WC (2009) 9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation. J Med Chem 52:4743–4756PubMedGoogle Scholar
  126. 126.
    Huang W, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC (2010) Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl]benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 53:4701–4719PubMedGoogle Scholar
  127. 127.
    O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang W, Xu Q, Metcalf CA, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MWN, Druker BJ, Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412PubMedPubMedCentralGoogle Scholar
  128. 128.
    Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M (2012) Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 367:2075–2088PubMedPubMedCentralGoogle Scholar
  129. 129.
    Cortes JE, Kim DW, Pinilla-Ibarz J, Le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796PubMedGoogle Scholar
  130. 130.
    Iclusig [package insert] (2012) ARIAD Pharmaceuticals, Cambridge, MAGoogle Scholar
  131. 131.
    Fava C, Morotti A, Dogliotti I, Saglio G, Rege-Cambrin G (2015) Update on emerging treatments for chronic myeloid leukemia. Expert Opin Emerg Drugs 20:183–196PubMedGoogle Scholar
  132. 132.
    Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, Le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW (2016) Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol 17:612–621PubMedGoogle Scholar
  133. 133.
    Manley PW, Bruggen J, Floersheimer A, Furet P, Jensen MR, Mestan J, Pissot C, Cowan-Jacob S (2008) Rational design of T315I BCR-Abl inhibitors for the treatment of chronic myelogenous leukemia (CML): BGG463. In: Abstracts of the fall meeting of the Swiss Chemical Society, Zurich, Switzerland, 11 Sept 2008. Chimia 62(7–8):579. Abstr 88Google Scholar
  134. 134.
    Andraos R, Qian Z, Bonenfant D, Rubert J, Vangrevelinghe E, Scheufler C, Marque F, Régnier CH, De Pover A, Ryckelynck H, Bhagwat N, Koppikar P, Goel A, Wyder L, Tavares G, Baffert F, Pissot-Soldermann C, Manley PW, Gaul C, Voshol H, Levine RL, Sellers WR, Hofmann F, Radimerski T (2012) Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov 2:512–523PubMedPubMedCentralGoogle Scholar
  135. 135.
    Ren P, Wang X, Zhang G, Ding Q, You S, Zhang Q, Chopiuk G, Pamela A, Sim T, Gray NS (2005) Preparation of imidazolylpyrimidinamines as protein kinase inhibitors. PCT Int Appl WO 2005123719, 29 Dec 2005Google Scholar
  136. 136.
    Choi HG, Ren P, Adrian F, Sun F, Lee HS, Wang X, Ding Q, Zhang G, Xie Y, Zhang J, Liu Y, Tove T, Warmuth M, Manley PW, Mestan J, Gray NS, Sim T (2010) A type-II kinase inhibitor capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl. J Med Chem 53:5439–5448PubMedPubMedCentralGoogle Scholar
  137. 137.
    Adrian FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley PW, Mestan J, Fabbro D, Gray NS (2006) Allosteric inhibitors of Bcr-Abl-dependent cell proliferation. Nat Chem Biol 2:95–102PubMedGoogle Scholar
  138. 138.
    Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu L, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010) Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501–506PubMedPubMedCentralGoogle Scholar
  139. 139.
    Choi Y, Seeliger MA, Panjarian SB, Kim H, Deng X, Sim T, Couch B, Koleske AJ, Smithgall TE, Gray NS (2009) N-Myristoylated c-Abl tyrosine kinase localizes to the endoplasmic reticulum upon binding to an allosteric inhibitor. J Biol Chem 284:29005–29014PubMedPubMedCentralGoogle Scholar
  140. 140.
    Deng X, Okram B, Ding Q, Zhang J, Choi Y, Adrian FJ, Wojciechowski A, Zhang G, Che J, Bursulaya B, Cowan-Jacob SW, Rummel G, Sim T, Gray NS (2010) Expanding the diversity of allosteric Bcr-Abl inhibitors. J Med Chem 53:6934–6946PubMedPubMedCentralGoogle Scholar
  141. 141.
    Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL (2010) Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc 132:7043–7048PubMedGoogle Scholar
  142. 142.
    Schoepfer J, Berellini G, Cai H, Caravatti G, Dodd S, Furet P, Gangal G, Grotzfeld RM, Quamrul HA, Hood T, Cowan-Jacob S, Jahnke W, Loo A, Manley PW, Pelle X, Salem B, Sharma S, Zhu W, Marzinzik A, Gabriel T, Keen N, Petruzzelli L, Vanasse G, Sellers WR, Wylie A (2015) Discovery and pharmacological properties of ABL001, a novel potent and specific BCR-ABL allosteric inhibitor. In: Abstracts of the 250th American Chemical Society national meeting, Boston, MA, 16-20 Aug 2015, MEDI-285Google Scholar
  143. 143.
    Xu G, Shen H, Tong T, Lu A, Gou S (2010) Synthesis, crystal structure, and spectral characterization of flumatinib mesylate. Synth Comm 40:2564–2570Google Scholar
  144. 144.
    Kim S, Menon H, Jootar S, Saikia T, Kwak J, Sohn S, Park JS, Jeong SH, Kim HJ, Kim Y, Oh SJ, Kim H, Zang DY, Chung JS, Shin HJ, Do YR, Kim J, Kim D, Choi CW, Park S, Park HL, Lee GL, Cho DJ, Shin JS, Kim D (2014) Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica 99:1191–1196PubMedPubMedCentralGoogle Scholar
  145. 145.
    Chan WW, Wise SC, Kaufman MD, Ahn Y, Ensinger CL, Haack T, Hood MM, Jones J, Lord JW, Lu W, Miller D, Patt WC, Smith BD, Petillo PA, Rutkoski TJ, Telikepalli H, Vogeti L, Yao T, Chun L, Clark R, Evangelista P, Gavrilescu LC, Lazarides K, Zaleskas VM, Stewart LJ, Van Etten RA, Flynn DL (2011) Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 19:556–568PubMedPubMedCentralGoogle Scholar
  146. 146.
    Gugliotta G, Castagnetti F, Fogli M, Cavo M, Baccarani M, Rosti G (2013) Impact of comorbidities on the treatment of chronic myeloid leukemia with tyrosine-kinase inhibitors. Expert Rev Hematol 6:563–574PubMedGoogle Scholar
  147. 147.
    Efficace F, Cannella L (2016) The value of quality of life assessment in chronic myeloid leukemia patients receiving tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program 206:170–179Google Scholar
  148. 148.
    Pavlu J, Szydlo RM, Goldman JM, Apperley JF (2011) Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 117:755–763PubMedGoogle Scholar
  149. 149.
    Yong ASM, Eolia Brissot E, Rubinstein S, Savani BN, Mohty M (2015) Transplant to treatment-free remission: the evolving view of ‘cure’ in chronic myeloid leukemia. Expert Rev Hematol 8:785–797PubMedGoogle Scholar
  150. 150.
    Mahon F-X (2015) Discontinuation of tyrosine kinase therapy in CML. Ann Hematol 94(Suppl 2):S187–S193PubMedGoogle Scholar
  151. 151.
    Hughes TP, Ross DM (2016) Moving treatment-free remission into mainstream clinical practice in CML. Blood 128:17–23PubMedGoogle Scholar
  152. 152.
    Vonka V, Petráĉková M (2015) Immunology of chronic myeloid leukemia: current concepts and future goals. Expert Rev Clin Immunol 11:511–522PubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Global Discovery ChemistryNovartis Institutes for Biomedical ResearchBaselSwitzerland

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