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FLT3激酶抑制剂及其在急性髓系白血病治疗领域的研究进展

李同辉, 郭昊, 陆涛, 王越, 卢帅, 唐伟方

李同辉, 郭昊, 陆涛, 王越, 卢帅, 唐伟方. FLT3激酶抑制剂及其在急性髓系白血病治疗领域的研究进展[J]. 中国药科大学学报, 2015, 46(2): 153-161. DOI: 10.11665/j.issn.1000-5048.20150203
引用本文: 李同辉, 郭昊, 陆涛, 王越, 卢帅, 唐伟方. FLT3激酶抑制剂及其在急性髓系白血病治疗领域的研究进展[J]. 中国药科大学学报, 2015, 46(2): 153-161. DOI: 10.11665/j.issn.1000-5048.20150203
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LI Tonghui, GUO Hao, LU Tao, WANG Yue, LU Shuai, TANG Weifang. Advances in the research of FLT3 inhibitors for acute myeloid leukemia[J]. Journal of China Pharmaceutical University, 2015, 46(2): 153-161. DOI: 10.11665/j.issn.1000-5048.20150203
Citation: LI Tonghui, GUO Hao, LU Tao, WANG Yue, LU Shuai, TANG Weifang. Advances in the research of FLT3 inhibitors for acute myeloid leukemia[J]. Journal of China Pharmaceutical University, 2015, 46(2): 153-161. DOI: 10.11665/j.issn.1000-5048.20150203
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FLT3激酶抑制剂及其在急性髓系白血病治疗领域的研究进展

  • 1.

    中国药科大学有机化学教研室

  • 2.

    中国药科大学无机化学教研室

基金项目: 国家自然科学基金资助项目(No.81172933)

Advances in the research of FLT3 inhibitors for acute myeloid leukemia

摘要

    摘要
  • 摘要: 急性髓系细胞白血病(AML)是成年人最常见的急性白血病，FMS样酪氨酸激酶3(FLT3)突变是AML中发现的第1个突变，其所引发的AML预后甚差。近年来，一些FLT3靶向抑制剂显示出了对体内FLT3信号通路传导的抑制，为AML的治疗提供了新途径。本文对FLT3激酶抑制剂，按结构分成吲哚酮类、吲哚并咔唑类、苯并咪唑/吡唑类、喹啉、喹喔啉和喹唑啉类、三环类、嘧啶类等共7类进行综述。
    Abstract: Acute myeloid leukemia(AML)is one of the most common acute leukemias in adults. Those patients with FLT3 mutations have a particularly poor prognosis. Recently, the emergence of a variety of targeted inhibitors has shown the capability of suppressing FLT3 signaling in vivo, which provided a new way to treat AML. In this paper, we reviewed those inhibitors based on their structures, which include indolone-related inhibitors, indolocarbazo-related inhibitors, benzimidazole/benzopyrazole-related inhibitors, quinoline/quinoxaline/quinazoline-related inhibitors, tricyclic inhibitors, pyrimidine-related inhibitors and others.
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  • [1] Howlader N, Noone AM, Krapcho M, et al. SEER stat fact sheets:acute myeloid leukemia[EB/OL].2013.http://seer.cancer.gov/csr/1975_2010/.
    [2] Lowenberg B,Downing JR,Burnett A.Acute myeloid leukemia[J].N Engl J Med,1999,341(14):1051-1062.
    [3] Kelly LM, Gilliland DG. Genetics of myeloid leukemias[J].Annu Rev Genomics Hum Genet,2002,3(1):179-198.
    [4] Ley T,Miller C,Ding L,et al.Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia[J].N Engl J Med,2013,368(22):2059-2074.
    [5] Gilliland DG,Griffin JD.The roles of FLT3 in hematopoiesis and leukemia[J].Blood,2002,100(5):1532-1542.
    [6] Geer PV,Hunter T,Lindberg RA.Receptor protein-tyrosine kinases and their signal transduction pathways[J].Ann Rev Cell Biol,1994,10(1):251-337.
    [7] Carow CE,Kim E,Hawkins AL,et al.Localization of the human stem cell tyrosine kinase-1 gene(FLT3)to 13q12→ q13[J].Cytogenet Genome Res,1995,70(3/4):255-257.
    [8] Lyman S,James L,Johnson L,et al.Cloning of the human homologue of the murine FLT3 ligand:a growth factor for early hematopoietic progenitor cells[J].Blood,1994,83(10): 2795-2801.
    [9] Small D,Levenstein M,Kim E,et al.STK-1,the human homolog of Flk-2/Flt-3,is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells[J]. Proc Natl Acad Sci U S A, 1994,91(2): 459-463.
    [10] Hay N,Sonenberg N.Upstream and downstream of mTOR[J]. Genes Dev,2004,18(16): 1926-1945.
    [11] Roux PP,Blenis J.ERK and p38 MAPK-activated protein kinases:a family of protein kinases with diverse biological functions[J].Microbiol Mol Biol Rev,2004,68(2):320-344.
    [12] Manning BD,Cantley LC.AKT/PKB signaling:navigating downstream[J].Cell,2007,129(7):1261-1274.
    [13] Bar-Natan M,Nelson EA,Xiang M,et al.STAT signaling in the pathogenesis and treatment of myeloid malignancies[J].JAK-STAT,2012,1(2):55-64.
    [14] Carow C,Levenstein M,Kaufmann S,et al.Expression of the hematopoietic growth factor receptor FLT3 (STK-1/FLK2)in human leukemias[J].Blood,1996,87(3):1089-1096.
    [15] Rosnet O,Bühring HJ,Marchetto S,et al.Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells[J].Leukemia,1996,10(2):238-248.
    [16] Kiyoi H,Towatari M,Yokota S,et al.Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product[J].Leukemia,1998,12(9):1333-1337.
    [17] Nakao M,Yokota S,Iwai T,et al.Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia[J].Leukemia,1996,10(12):1911-1918.
    [18] Kayser S,Schlenk RF,Londono MC,et al.Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome[J].Blood,2009,114(12):2386-2392.
    [19] Marcucci G,Haferlach T,Döhner H.Molecular genetics of adult acute myeloid leukemia:prognostic and therapeutic implications[J].Clin Oncol,2011, 29(5):475-486.
    [20] Schnittger S,Bacher U,Haferlach C,et al.Diversity of the juxtamembrane and TKD1 mutations(exons 13-15)in the FLT3 gene with regards to mutant load,sequence,length,localization,and correlation with biological data[J].Genes Chromosomes Cancer,2012,51(10):910-924.
    [21] Levis M,Small D.FLT3:ITDoes matter in leukemia[J].Leukemia,2003,17(9):1738-1752.
    [22] Stirewalt DL,Kopecky KJ,Meshinchi S,et al.Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia[J].Blood,2006,107(9):3724-3726.
    [23] Thiede C,Steudel C,Mohr B,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[J].Blood,2002,99(12):4326-4335.
    [24] Pratz KW,Sato T,Murphy KM,et al.FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML[J].Blood,2010,115(7):1425-1432.
    [25] Abu‐Duhier FM,Goodeve AC,Wilson GA,et al.Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia[J].Br J Haematol,2001,113(4):983-988.
    [26] Yamamoto Y,Kiyoi H,Nakano Y,et al.Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies[J].Blood,2001,97(8):2434-2439.
    [27] Moreno I,Martín G,Bolufer P,et al.Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia[J].Haematologica,2003,88(1):19-24.
    [28] Gale RE,Green C,Allen C,et al.The impact of FLT3 internal tandem duplication mutant level,number,size,and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia[J].Blood,2008,111(5):2776-2784.
    [29] Schnittger S,Bacher U,Kern W,et al.Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia[J].Leuke-mia,2011, 25(8):1297-1304.
    [30] Kancha RK,Grundler R,Peschel C,et al.Sensitivity toward sorafenib and sunitinib varies between different activating and drug-resistant FLT3-ITD mutations[J].Exp Hematol,2007,35(10):1522-1526.
    [31] Fiedler W,Kayser S,Kebenko 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[J].Blood,2005,105(3):986-993.
    [32] Motzer R.,Hutson T,Tomczak P,et al.Sunitinib versus interferon alfa in metastatic renal-cellcarcinoma[J].N Engl J Med,2007,356(2):115-124.
    [33] Demetri GD,van Oosterom AT,Garrett CR,et al.Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib:a randomised controlled trial[J].Lancet,2006,368(9544):1329-1338.
    [34] Stone RM,DeAngelo DJ,Klimek V,et al.Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor,PKC412 [J].Blood,2005,105(1):54-60.
    [35] Fischer T,Stone RM,DeAngelo DJ,et al.Phase IIB trial of oral Midostaurin(PKC412),the FMS-like tyrosine kinase 3 receptor(FLT3)and multi-targeted kinase inhibitor,in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3[J].J Clin Oncol,2010,28(28):4339-4345.
    [36] Stone R,Fischer T,Paquette R,et al.Phase Ib study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adultpatients with acute myeloid leukemia[J].Leukemia,2012,26(9):2061-2068.
    [37] Smith BD,Levis M,Beran M,et al.Single-agent CEP-701,a novel FLT3 inhibitor,shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia[J].Blood,2004,103(10):3669-3676.
    [38] Knapper S,Burnett A,Littlewood T,et al.A phase 2 trial of the FLT3 inhibitor lestaurtinib(CEP701)as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy[J].Blood,2006,108(10):3262-3270.
    [39] Levis M,Ravandi F,Wang ES,et al.Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse[J].Blood,2011,117(12):3294-3301.
    [40] Hayley Ma,Bao Nguyen,Li Li,et al.TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo[J].Blood,2015,123(10):1525-1534.
    [41] Howard S,Berdini V,Boulstridge JA,et al.Fragment-based discovery of the pyrazol-4-yl urea(AT9283),a multitargeted kinase inhibitor with potent aurora kinase activity[J].J Med Chem,2008,52(2):379-388.
    [42] Pratz KW,Cortes J,Roboz GJ,et al.A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response[J].Blood,2009,113(17):3938-3946.
    [43] Kelly LM,YuJ C,Boulton CL,et al.CT53518,a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia(AML)[J].Cancer Cell,2002,1(5):421-432.
    [44] Pandey A,Volkots D L,Seroogy JM,et al.Identification of orally active,potent,and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family[J].J Med Chem,2002,45(17):3772-3793.
    [45] DeAngelo DJ,Stone RM,Heaney ML,et al.Phase 1 clinical results with tandutinib(MLN518),a novel FLT3 antagonist,in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome:safety,pharmacokinetics,and pharmacodynamics[J].Blood,2006,108(12):3674-3681.
    [46] Smith CC,Lasater E,Mccreery M,et al.Crenolanib(CP-868596)is a potent and selective type I FLT3 inhibitor that retains activity against AC220 resistancecausing FLT3 kinase domain mutants[J].Blood(ASH Annual Meeting Abstracts),2012,120(21):141.
    [47] Galanis A,Rajkhowa T,Muralidhara C,et al.Crenolanib:a next generation FLT3 inhibitor[J].Cancer Res,2012,72(8):3660.
    [48] Zimmerman E,Turner D,Buaboonnam J,et al.Crenolanib is active against models of drug-resistant FLT3-ITD positive acute myeloid leukemia[J].Blood,2013,122(22):3607-3615.
    [49] Smith DC,Smith MR,Sweeney C,et al.Cabozantinib in patients with advanced prostate cancer:results of a phase II randomized discontinuation trial[J].J Clin Oncol,2013,31(4):412-419.
    [50] Kurzrock R,Sherman SI,Ball DW,et al.Activity of XL184 (Cabozantinib),an oral tyrosine kinase inhibitor,in patients with medullary thyroid cancer[J].J Clin Oncol,2011,29(19):2660-2666.
    [51] Renhowe PA,Pecchi S,Shafer CM,et al.Design,structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones:a novel class of receptor tyrosine kinase inhibitors[J].J Med Chem,2008,52(2):278-292.
    [52] Wang X,Kay A,Anak O,et al.Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib[J].J Clin Pharmacol J New Drugs,2013,53(1):14-20.
    [53] Chung TW,Chen CH,Lin CC,et al.Exploring a sulfone linker utilizing trimethyl aluminum as a cleavage reagent:solid-phase synthesis of sulfonamides and ureas[J].Mol Divers,2012,16(3):463-476.
    [54] Albers C,Leischner H,Verbeek M,et al.The secondary FLT3-ITD F691L mutation induces resistance to AC220 in FLT3-ITD+AML but retains in vitro sensitivity to PKC412 and Sunitinib[J].Leukemia,2013,27(6):1416-1418.
    [55] Cortes J E,Kantarjian H,Foran J M,et al.Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status[J].J Clin Oncol,2013,31(29):3681-3687.
    [56] Cortes JE,Perl AE,Dombret H,et al.Final results of a phase 2 open-label,monotherapy efficacy and safety study of quizartinib(AC220)in patient 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia[C]//ASH Annual Meeting Abstracts,2012,120(21):48.
    [57] Levis MJ,Perl AE,Dombret H,et al.Final results of a phase 2 open-label,monotherapy efficacy and safety study of quizartinib(AC220)in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation[C]//ASH Annual Meeting Abstracts,2012,120(21):673.
    [58] Hart S,Goh KC,Novotny-Diermayr V,et al.SB1518,a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies[J].Leukemia,2011,25(11):1751-1759.
    [59] Poulsen A,William A,Blanchard S,et al.Structure-based design of oxygen-linked macrocyclic kinase inhibitors:discovery of SB1518 and SB1578,potent inhibitors of Janus kinase 2 (JAK2)and Fms-like tyrosine kinase-3 (FLT3)[J].J Comput Aided Mol Des,2012,26(4):437-450.
    [60] Hart S, Goh KC, Novotny-Diermayr V, et al. Pacritinib(SB1518),a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia[J].Blood Cancer J,2011,1(11):e44.
    [61] Fletcher GC,Brokx RD,Denny TA,et al.ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action[J].Mol Cancer Ther,2011,10(1):126-137.
    [62] Wilhelm SM,Carter C,Tang LY,et al.BAY43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J].Cancer Res,2004,64(19):7099-7109.
    [63] Escudier B,Eisen T,Stadler WM,et al.Sorafenib in advanced clear-cell renal-cell carcinoma[J].N Engl J Med,2007,356(2):125-134.
    [64] Llovet JM,Ricci S,Mazzaferro V,et al.Sorafenib in advanced hepatocellular carcinoma[J].N Engl J Med,2008,359(4):378-390.
    [65] Zhang W,Konopleva M,Shi YX,et al.Mutant FLT3:a direct target of sorafenib in acute myelogenous leukemia[J].Natl Cancer Inst,2008,100(3):184-198.
    [66] Pratz K,Cho E,Levis M,et al.A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias[J].Leukemia,2010,24(8):1437-1444.
    [67] Metzelder S,Schroeder T,Finck A,et al.High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses[J].Leukemia,2012,26(11):2353-2359.
    [68] Jain P,Kantarjian H,Cortes J.Chronic myeloid leukemia:overview of new agents and comparative analysis[J].Curr Treat Options Oncol,2013,14(2):127-143.
    [69] Lee HK, Kim HW, Lee IY, et al. G-749, a novel FLT3 kinase inhibitor,can overcome drug resistance for the treatment of acute myeloid leukemia[J].Blood,2014,123(14):2209-2219.
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  • 刊出日期:  2015-04-24

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