JAK2抑制剂治疗骨髓增殖性肿瘤研究进展
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摘要
骨髓增殖性肿瘤(myelopro1iferative neoplasms, MPNs)是一类造血干细胞异常增生性疾病,主要表现为骨髓中一系或多系细胞出现异常增殖。JAK2磷酸化导致的JAK-STAT信号通路持续活化是诱发MPNs的重要原因,而JAK2激酶的突变可以使其处于持续的磷酸化状态, JAK2最典型的突变是假激酶区V617F的位点突变。95%的红细胞增多症(PV)以及50%的原发性骨髓纤维化(PMF)、血小板增多症(ET)患者中存在这种突变。现已明确JAK2是治疗MPNs的重要靶标,通过抑制JAK2-STAT信号通路的异常激活来治疗MPNs已成为热门研究方向。本文拟从JAK2激酶的生物学功能、JAK2与MPNs的关系以及JAK2小分子抑制剂的研发现状等角度,综述近年来JAK2抑制剂在治疗MPNs疾病的研究进展。
Myeloproliferative neoplasms(MPNs) result from clonal expansion of haematopoietic stem cells and are characterized by abnormal proliferation of myeloid lineage cells in the bone marrow. Sustained activation of JAK-STAT signaling pathway due to JAK2 phosphorylation is an important cause of MPNs, and mutation of JAK2 kinase can keep it in a state of continuous phosphorylation. The most typical mutation in JAK2 is a site mutation of V617 F in the pseudokinase domain. The JAK2 V617 F-activating mutation is highly prevalent in MPNs,with frequencies estimated at approximately 95% in polycythaemia vera(PV) and 50% in primary myelofibrosis(PMF) and essential thrombocytosis(ET) patients. It is now clear that JAK2 is an important target for treatment of MPNs. Inhibiting aberrant activation of the JAK2-STAT signaling pathway has become a popular trend in research for effective treatment of MPNs. This review summarizes the research progress in developing JAK2 inhibitors for treatment of MPNs in recent years, including the new discoveries of the biological functions of JAK2, the relationship between JAK2 and MPN, and the status of development of JAK2 small molecule inhibitors.
Myeloproliferative neoplasms(MPNs) result from clonal expansion of haematopoietic stem cells and are characterized by abnormal proliferation of myeloid lineage cells in the bone marrow. Sustained activation of JAK-STAT signaling pathway due to JAK2 phosphorylation is an important cause of MPNs, and mutation of JAK2 kinase can keep it in a state of continuous phosphorylation. The most typical mutation in JAK2 is a site mutation of V617 F in the pseudokinase domain. The JAK2 V617 F-activating mutation is highly prevalent in MPNs,with frequencies estimated at approximately 95% in polycythaemia vera(PV) and 50% in primary myelofibrosis(PMF) and essential thrombocytosis(ET) patients. It is now clear that JAK2 is an important target for treatment of MPNs. Inhibiting aberrant activation of the JAK2-STAT signaling pathway has become a popular trend in research for effective treatment of MPNs. This review summarizes the research progress in developing JAK2 inhibitors for treatment of MPNs in recent years, including the new discoveries of the biological functions of JAK2, the relationship between JAK2 and MPN, and the status of development of JAK2 small molecule inhibitors.
引文
[1] Ihle JN. The Janus protein tyrosine kinases in hematopoietic cytokine signaling[J]. Semin Immunol, 1995, 7:247-254.
[2] Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis[J].N Engl J Med, 2012, 366:787-798.
[3] Waldmann TA, Chen J. Disorders of the JAK/STAT pathway in T cell lymphoma pathogenesis:implications for immunotherapy[J]. Annu Rev Immunol, 2017, 35:533-550.
[4] Leonard WJ, O'Shea JJ. JAKS and STATs:biological implications[J]. Annu Rev Immunol, 1998, 16:293-322.
[5] Gadina M. Janus kinases:an ideal target for the treatment of autoimmune diseases[J]. J Investig Dermatol Symp Proc, 2013,16:S70-S72.
[6] Ferrao R, Lupardus PJ. The Janus kinase(JAK)FERM and SH2domains:bringing specificity to JAK-receptor interactions[J].Front Endocrinol, 2017, 8:71.
[7] Toms AV, Deshpande A, McNally R, et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of JAK kinases[J]. Nat Struct Mol Biol, 2013, 20:1221-1223.
[8] Ungureanu D, Wu JH, Pekkala T, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling[J]. Nat Struct Mol Biol, 2011, 18:971-976.
[9] Zimran E, Hoffman R, Kremyanskaya M. Current approaches to challenging scenarios in myeloproliferative neoplasms[J].Expert Rev Anticancer Ther, 2018, 18:567-578.
[10] Mullally A, Lane SW, Ball B, et al. Physiological JAK2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells[J]. Cancer Cell, 2010, 17:584-596.
[11] Harrison DA. The JAK/STAT pathway[J]. Cold Spring Harb Perspect Biol, 2012. DOI:10.1101/cshperspect.a011205.
[12] Yu H, Jove R. The STATs of cancer--new molecular targets come of age[J]. Nat Rev Cancer, 2004, 4:97-105.
[13] Yuliantie E, Dai XC, Yang DH, et al. High-throughput screening for small molecule inhibitors of the type-I interferon signaling pathway[J]. Acta Pharm Sin B, 2018, 8:889-899.
[14] Vera J, Rateitschak K, Lange F, et al. Systems biology of JAKSTAT signalling in human malignancies[J]. Prog Biophys Mol Biol, 2011, 106:426-434.
[15] Hubbard SR. Mechanistic insights into regulation of JAK2tyrosine kinase[J]. Front Endocrinol, 2017, 8:361.
[16] Passamonti F, Maffioli M. Update from the latest WHO classification of MPNs:a user's manual[J]. Hematology Am Soc Hematol Educ Program, 2016, 2016:534-542.
[17] Passamonti F, Mora B, Giorgino T, et al. Driver mutations'effect in secondary myelofibrosis:an international multicenter study based on 781 patients[J]. Leukemia, 2017, 31:970-973.
[18] Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis[J].Cancer Cell, 2005,7:387-397.
[19] Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders[J]. Lancet, 2005, 365:1054-1061.
[20] Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders[J]. N Engl J Med, 2005,352:1779-1790.
[21] James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2mutation leading to constitutive signalling causes polycythaemia vera[J]. Nature, 2005, 434:1144-1148.
[22] Pietra D, Li S, Brisci A, et al. Somatic mutations of JAK2 exon12 in patients with JAK2(V617F)-negative myeloproliferative disorders[J]. Blood, 2008, 111:1686-1689.
[23] Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis[J]. N Engl J Med, 2007, 356:459-468.
[24] Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia[J]. PLoS Med, 2006, 3:e270.
[25] Cabagnols X, Cayuela JM, Vainchenker W. A CALR mutation preceding BCR-ABL1 in an atypical myeloproliferative neoplasm[J]. N Engl J Med, 2015, 372:688-690.
[26] Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis[J].Blood,2014, 123:e123-e133.
[27] Leroy E, Constantinescu SN. Rethinking JAK2 inhibition:towards novel strategies of more specific and versatile Janus kinase inhibition[J]. Leukemia, 2017, 31:1023-1038.
[28] Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera[J]. N Engl J Med, 2015, 372:426-435.
[29] Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias(PERSIST-1):an international, randomised,phase 3 trial[J]. Lancet Haematol, 2017, 4:e225-e236.
[30] Verstovsek S, Courby S, Griesshammer M, et al. A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia[J]. Leuk Res, 2017, 60:11-17.
[31] Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1:a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis[J]. J Clin Oncol,2017, 35:3844-3850.
[32] Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis:a randomized clinical trial[J]. JAMA Oncol, 2015, 1:643-651.
[33] Verstovsek S, Hoffman R, Mascarenhas J, et al. A phase I, openlabel, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis[J]. Leuk Res, 2015, 39:157-163.
[34] Verstovsek S, Mesa RA, Salama ME, et al. A phase 1 study of the Janus kinase 2(JAK2)V617F inhibitor, gandotinib(LY2784544),in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia[J]. Leuk Res, 2017, 61:89-95.
[35] Berdeja J, Palandri F, Baer MR, et al. Phase 2 study of gandotinib(LY2784544)in patients with myeloproliferative neoplasms[J].Leuk Res,2018, 71:82-88.
[36] Verstovsek S, Talpaz M, Ritchie E, et al. A phase I, open-label,dose-escalation, multicenter study of the JAK2 inhibitor NS-018in patients with myelofibrosis[J]. Leukemia, 2017, 31:393-402.
[37] Meyer SC, Keller MD, Chiu S, et al. CHZ868, a typeⅡJAK2inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms[J]. Cancer Cell,2015,28:15-28.
[38] Andraos R, Qian ZY, Bonenfant D, et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent[J]. Cancer Discov, 2012, 2:512-523.
[39] Lipka DB, Hoffmann LS, Heidel F, et al. LS104, a non-ATPcompetitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells[J]. Mol Cancer Ther,2008, 7:1176-1184.
[40] Jatiani SS, Cosenza SC, Reddy MV, et al. A non-ATP-competitive dual inhibitor of JAK2V617F and BCR-ABLT315I kinases:elucidation of a novel therapeutic spectrum based on substrate competitive inhibition[J]. Genes Cancer, 2010, 1:331-345.
[41] Blanc J, Geney R, Menet C. TypeⅡkinase inhibitors:an opportunity in cancer for rational design[J]. Anticancer Agents Med Chem, 2013, 13:731-747.
[42] Samanta AK, Chakraborty SN, Wang Y, et al. Destabilization of Bcr-Abl/JAK2 network by a JAK2/Abl kinase inhibitor ON044580 overcomes drug resistance in blast crisis chronic myelogenous leukemia(CML)[J]. Genes Cancer, 2010, 1:346-359.
[43] Hu M, Xu CB, Yang C, et al. Discovery and evaluation of ZT55,a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms[J]. J Exp Clin Cancer Res,2019,38:49.
[44] Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis?[J]. Blood, 2017, 129:832-837.
[45] Verstovsek S, Gotlib J, Mesa RA,et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis:COMFORT-Ⅰand-Ⅱpooled analyses[J]. J Hematol Oncol, 2017, 10:156.
[46] Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis:a randomized clinical trial[J]. JAMA Oncol, 2018, 4:652-659.
[47] Neubauer H, Cumano A, Muller M, et al. JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis[J]. Cell, 1998, 93:397-409.
[48] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis[J]. N Engl J Med, 2010, 363:1117-1127.
[49] Komrokji RS, Seymour JF, Roberts AW, et al. Results of a phase2 study of pacritinib(SB 1518), a JAK2/JAK2(V617F)inhibitor,in patients with myelofibrosis[J]. Blood, 2015, 125:2649-2655.
[50] Verstovsek S, Odenike O, Singer JW, et al. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofi-brosis or other myeloid malignancies[J]. J Hematol Oncol,2016,9:137.
[51] Tremblay D, Mascarenhas J. Pacritinib to treat myelofibrosis patients with thrombocytopenia[J]. Expert Rev Hematol, 2018,11:707-714.
[52] Moran N. Incyte comes of age with JAK inhibitor approval[J].Nat Biotechnol, 2012, 30:3-5.
[53] Zheng J, Xin Y, Zhang JY, et al. Pharmacokinetics and disposition of momelotinib revealed a disproportionate human metabolite-resolution for clinical development[J]. Drug Metab Dispos,2018,46:237-247.
[54] Asshoff M, Petzer V, Warr MR, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents[J]. Blood, 2017, 129:1823-1830.
[55] Saeed I, McLornan D, Harrison CN. Managing side effects of JAK inhibitors for myelofibrosis in clinical practice[J]. Expert Rev Hematol, 2017, 10:617-625.
[56] Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib(JAKARTA-2):a single-arm, open-label,non-randomised, phase 2, multicentre study[J]. Lancet Haematol,2017,4:e317-e324.
[57] Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis[J]. JClin Oncol,2011,29:789-796.
[58] Gowin K, Kosiorek H, Dueck A, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis[J]. Leuk Res, 2017, 60:31-35.
[59] Andrei M, Sindhu H, Wang JC. Two cases of myelofibrosis with severe thrombocytopenia and symptomatology successfully treated with combination of pomalidomide and ruxolitinib[J].Leuk Lymphoma, 2015, 56:524-526.
[60] Bjrn ME, De Stricker K, Kjaer L, et al. Combination therapy with interferon and JAK1-2 inhibitor is feasible:proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera[J]. Leuk Res Rep, 2014, 3:73-75.
[61] Durrant ST, Nagler A, Vannucchi AM, et al. An open-label,multicenter, 2-Arm, dose-finding, phase 1b study of the combination of ruxolitinib and buparlisib(BKM120)in patients with myelofibrosis:results from HARMONY study[J]. Blood, 2015,126:827.
[62] Bjrn ME, Hasselbalch HC. Minimal residual disease or cure in MPNs? Rationales and perspectives on combination therapy with interferon-alpha2 and ruxolitinib[J]. Expert Rev Hematol,2017, 10:393-404.
[63] Bartalucci N, Tozzi L, Bogani C, et al. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms[J]. J Cell Mol Med, 2013, 17:1385-1396.
[2] Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis[J].N Engl J Med, 2012, 366:787-798.
[3] Waldmann TA, Chen J. Disorders of the JAK/STAT pathway in T cell lymphoma pathogenesis:implications for immunotherapy[J]. Annu Rev Immunol, 2017, 35:533-550.
[4] Leonard WJ, O'Shea JJ. JAKS and STATs:biological implications[J]. Annu Rev Immunol, 1998, 16:293-322.
[5] Gadina M. Janus kinases:an ideal target for the treatment of autoimmune diseases[J]. J Investig Dermatol Symp Proc, 2013,16:S70-S72.
[6] Ferrao R, Lupardus PJ. The Janus kinase(JAK)FERM and SH2domains:bringing specificity to JAK-receptor interactions[J].Front Endocrinol, 2017, 8:71.
[7] Toms AV, Deshpande A, McNally R, et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of JAK kinases[J]. Nat Struct Mol Biol, 2013, 20:1221-1223.
[8] Ungureanu D, Wu JH, Pekkala T, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling[J]. Nat Struct Mol Biol, 2011, 18:971-976.
[9] Zimran E, Hoffman R, Kremyanskaya M. Current approaches to challenging scenarios in myeloproliferative neoplasms[J].Expert Rev Anticancer Ther, 2018, 18:567-578.
[10] Mullally A, Lane SW, Ball B, et al. Physiological JAK2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells[J]. Cancer Cell, 2010, 17:584-596.
[11] Harrison DA. The JAK/STAT pathway[J]. Cold Spring Harb Perspect Biol, 2012. DOI:10.1101/cshperspect.a011205.
[12] Yu H, Jove R. The STATs of cancer--new molecular targets come of age[J]. Nat Rev Cancer, 2004, 4:97-105.
[13] Yuliantie E, Dai XC, Yang DH, et al. High-throughput screening for small molecule inhibitors of the type-I interferon signaling pathway[J]. Acta Pharm Sin B, 2018, 8:889-899.
[14] Vera J, Rateitschak K, Lange F, et al. Systems biology of JAKSTAT signalling in human malignancies[J]. Prog Biophys Mol Biol, 2011, 106:426-434.
[15] Hubbard SR. Mechanistic insights into regulation of JAK2tyrosine kinase[J]. Front Endocrinol, 2017, 8:361.
[16] Passamonti F, Maffioli M. Update from the latest WHO classification of MPNs:a user's manual[J]. Hematology Am Soc Hematol Educ Program, 2016, 2016:534-542.
[17] Passamonti F, Mora B, Giorgino T, et al. Driver mutations'effect in secondary myelofibrosis:an international multicenter study based on 781 patients[J]. Leukemia, 2017, 31:970-973.
[18] Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis[J].Cancer Cell, 2005,7:387-397.
[19] Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders[J]. Lancet, 2005, 365:1054-1061.
[20] Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders[J]. N Engl J Med, 2005,352:1779-1790.
[21] James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2mutation leading to constitutive signalling causes polycythaemia vera[J]. Nature, 2005, 434:1144-1148.
[22] Pietra D, Li S, Brisci A, et al. Somatic mutations of JAK2 exon12 in patients with JAK2(V617F)-negative myeloproliferative disorders[J]. Blood, 2008, 111:1686-1689.
[23] Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis[J]. N Engl J Med, 2007, 356:459-468.
[24] Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia[J]. PLoS Med, 2006, 3:e270.
[25] Cabagnols X, Cayuela JM, Vainchenker W. A CALR mutation preceding BCR-ABL1 in an atypical myeloproliferative neoplasm[J]. N Engl J Med, 2015, 372:688-690.
[26] Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis[J].Blood,2014, 123:e123-e133.
[27] Leroy E, Constantinescu SN. Rethinking JAK2 inhibition:towards novel strategies of more specific and versatile Janus kinase inhibition[J]. Leukemia, 2017, 31:1023-1038.
[28] Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera[J]. N Engl J Med, 2015, 372:426-435.
[29] Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias(PERSIST-1):an international, randomised,phase 3 trial[J]. Lancet Haematol, 2017, 4:e225-e236.
[30] Verstovsek S, Courby S, Griesshammer M, et al. A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia[J]. Leuk Res, 2017, 60:11-17.
[31] Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1:a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis[J]. J Clin Oncol,2017, 35:3844-3850.
[32] Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis:a randomized clinical trial[J]. JAMA Oncol, 2015, 1:643-651.
[33] Verstovsek S, Hoffman R, Mascarenhas J, et al. A phase I, openlabel, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis[J]. Leuk Res, 2015, 39:157-163.
[34] Verstovsek S, Mesa RA, Salama ME, et al. A phase 1 study of the Janus kinase 2(JAK2)V617F inhibitor, gandotinib(LY2784544),in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia[J]. Leuk Res, 2017, 61:89-95.
[35] Berdeja J, Palandri F, Baer MR, et al. Phase 2 study of gandotinib(LY2784544)in patients with myeloproliferative neoplasms[J].Leuk Res,2018, 71:82-88.
[36] Verstovsek S, Talpaz M, Ritchie E, et al. A phase I, open-label,dose-escalation, multicenter study of the JAK2 inhibitor NS-018in patients with myelofibrosis[J]. Leukemia, 2017, 31:393-402.
[37] Meyer SC, Keller MD, Chiu S, et al. CHZ868, a typeⅡJAK2inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms[J]. Cancer Cell,2015,28:15-28.
[38] Andraos R, Qian ZY, Bonenfant D, et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent[J]. Cancer Discov, 2012, 2:512-523.
[39] Lipka DB, Hoffmann LS, Heidel F, et al. LS104, a non-ATPcompetitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells[J]. Mol Cancer Ther,2008, 7:1176-1184.
[40] Jatiani SS, Cosenza SC, Reddy MV, et al. A non-ATP-competitive dual inhibitor of JAK2V617F and BCR-ABLT315I kinases:elucidation of a novel therapeutic spectrum based on substrate competitive inhibition[J]. Genes Cancer, 2010, 1:331-345.
[41] Blanc J, Geney R, Menet C. TypeⅡkinase inhibitors:an opportunity in cancer for rational design[J]. Anticancer Agents Med Chem, 2013, 13:731-747.
[42] Samanta AK, Chakraborty SN, Wang Y, et al. Destabilization of Bcr-Abl/JAK2 network by a JAK2/Abl kinase inhibitor ON044580 overcomes drug resistance in blast crisis chronic myelogenous leukemia(CML)[J]. Genes Cancer, 2010, 1:346-359.
[43] Hu M, Xu CB, Yang C, et al. Discovery and evaluation of ZT55,a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms[J]. J Exp Clin Cancer Res,2019,38:49.
[44] Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis?[J]. Blood, 2017, 129:832-837.
[45] Verstovsek S, Gotlib J, Mesa RA,et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis:COMFORT-Ⅰand-Ⅱpooled analyses[J]. J Hematol Oncol, 2017, 10:156.
[46] Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis:a randomized clinical trial[J]. JAMA Oncol, 2018, 4:652-659.
[47] Neubauer H, Cumano A, Muller M, et al. JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis[J]. Cell, 1998, 93:397-409.
[48] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis[J]. N Engl J Med, 2010, 363:1117-1127.
[49] Komrokji RS, Seymour JF, Roberts AW, et al. Results of a phase2 study of pacritinib(SB 1518), a JAK2/JAK2(V617F)inhibitor,in patients with myelofibrosis[J]. Blood, 2015, 125:2649-2655.
[50] Verstovsek S, Odenike O, Singer JW, et al. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofi-brosis or other myeloid malignancies[J]. J Hematol Oncol,2016,9:137.
[51] Tremblay D, Mascarenhas J. Pacritinib to treat myelofibrosis patients with thrombocytopenia[J]. Expert Rev Hematol, 2018,11:707-714.
[52] Moran N. Incyte comes of age with JAK inhibitor approval[J].Nat Biotechnol, 2012, 30:3-5.
[53] Zheng J, Xin Y, Zhang JY, et al. Pharmacokinetics and disposition of momelotinib revealed a disproportionate human metabolite-resolution for clinical development[J]. Drug Metab Dispos,2018,46:237-247.
[54] Asshoff M, Petzer V, Warr MR, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents[J]. Blood, 2017, 129:1823-1830.
[55] Saeed I, McLornan D, Harrison CN. Managing side effects of JAK inhibitors for myelofibrosis in clinical practice[J]. Expert Rev Hematol, 2017, 10:617-625.
[56] Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib(JAKARTA-2):a single-arm, open-label,non-randomised, phase 2, multicentre study[J]. Lancet Haematol,2017,4:e317-e324.
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