Janus激酶及其抑制剂的研究进展
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摘要
Janus激酶(Janus kinases, JAKs)属于细胞因子受体相关的酪氨酸激酶家族,其介导的信号通路被不同细胞因子激活,在人体的生理活动中扮演着重要角色。该通路中蛋白的失活、突变以及过度表达会导致严重的疾病,包括自身免疫性疾病、肿瘤和血液疾病。因此,开发以JAKs为靶点的抑制剂,对于治疗上述疾病有着非常重要的临床意义。概述JAKs家族的结构、功能以及JAKs通路与疾病间的关系,着重介绍若干具有代表意义的JAKs抑制剂,并对其结构、靶点与适应证进行分析,为开发新型JAKs抑制剂提供思路。
The Janus kinases(JAKs) belong to the family of cytokine receptor-associated tyrosine kinases and mediate signaling pathway that can be activated by different cytokines, thus playing a critical role in the physiological activities of human body. The inactivation, mutation and overexpression of the proteins in this pathway will lead to severe symptoms including autoimmune diseases, malignant carcinoma and hematological disorders. Therefore, the development of JAKs-targeted inhibitors is of a great clinical significance for the treatment of these diseases. This paper briefly discussed the structure/function of the JAKs family and the relationship between JAKs signaling pathway and diseases, introduced representative JAKs inhibitors in detail and analyzed the structures, targets and indications of these inhibitors, providing new ideas for the development of novel JAKs inhibitors.
The Janus kinases(JAKs) belong to the family of cytokine receptor-associated tyrosine kinases and mediate signaling pathway that can be activated by different cytokines, thus playing a critical role in the physiological activities of human body. The inactivation, mutation and overexpression of the proteins in this pathway will lead to severe symptoms including autoimmune diseases, malignant carcinoma and hematological disorders. Therefore, the development of JAKs-targeted inhibitors is of a great clinical significance for the treatment of these diseases. This paper briefly discussed the structure/function of the JAKs family and the relationship between JAKs signaling pathway and diseases, introduced representative JAKs inhibitors in detail and analyzed the structures, targets and indications of these inhibitors, providing new ideas for the development of novel JAKs inhibitors.
引文
[1]Clark J D,Flanagan M E,Telliez J B.Discovery and development of Janus kinase(JAK)inhibitors for inflammatory diseases[J].J Med Chem,2014,57(12):5023-5038.
[2]Senkevitch E,Durum S.The promise of Janus kinase inhibitors in the treatment of hematological malignancies[J/OL].Cytokine,2017,98:33-41[2018-03-30].https://www.sciencedirect.com/science/article/abs/pii/S104346661630552X.Doi:10.1016/j.cyto.2016.10.012.
[3]Winthrop K L The emerging safety profile of JAK inhibitors in rheumatic disease[J].Nat Rev Rheumatol,2017,13(4):234-243.
[4]Roskoski R Jr.Janus kinase(JAK)inhibitors in the treatment of inflammatory and neoplastic diseases[J/OL].Pharmacol Res,2016,111:784-803[2018-03-30].https://www.sciencedirect.com/science/article/abs/pii/S1043661816307137.Doi:10.1016/j.phrs.2016.07.038.
[5]Babon J J,Lucet I S,Murphy J M,et al.The molecular regulation of Janus kinase(JAK)activation[J].Biochem J,2014,462(1):1-13.
[6]Wu W,Sun X H.Janus kinase 3:the controller and the controlled[J].Acta Biochim Biophys Sin(Shanghai),2012,44(3):187-196.
[7]Radtke S,Haan S,Jorissen A,et al.The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression[J].J Biol Chem,2005,280(27):25760-25768.
[8]Cai B,Cai J P,Luo Y L,et al.The specific roles of JAK/STAT signaling pathway in sepsis[J].Inflammation,2015,38(4):1599-1608.
[9]Scott L M,Gandhi M K.Deregulated JAK/STAT signalling in lymphomagenesis,and its implications for the development of new targeted therapies[J].Blood Rev,2015,29(6):405-415.
[10]Flamant M,Rigaill J,Paul S,et al.Advances in the development of Janus kinase inhibitors in inflammatory bowel disease:future prospects[J].Drugs,2017,77(10):1057-1068.
[11]Bose P,Verstovsek S.JAK2 inhibitors for myeloproliferative neoplasms:what is next?[J].Blood,2017,130(2):115-125.
[12]Babon J J,Lucet I S,Murphy J M,et al.The molecular regulation of Janus kinase(JAK)activation[J].Biochemical Journal,2014,462(1):1-13.
[13]Sun H B.Mechanical loading,cartilage degradation,and arthritis[J].Ann N Y Acad Sci,2010,1211(1):37-50.
[14]Tanaka Y.Recent progress and perspective in JAK inhibitors for rheumatoid arthritis:from bench to bedside[J].J Biochem,2015,158(3):173-179.
[15]Mascarenhas J O,Cross N C,Mesa R A.The future of JAK inhibition in myelofibrosis and beyond[J].Blood Rev,2014,28(5):189-196.
[16]Aittomaki S,Pesu M.Therapeutic targeting of the JAK/STATpathway[J].Basic Clin Pharmacol Toxicol,2014,114(1):18-23.
[17]Schwartz D M,Kanno Y,Villarino A,et al.JAK inhibition as a therapeutic strategy for immune and inflammatory diseases[J].Nat Rev Drug Discov,2017,16(12):843-862.
[18]Damsky W,King B A.JAK inhibitors in dermatology:the promise of a new drug class[J].J Am Acad Dermatol,2017,76(4):736-744.
[19]Schwartz D M,Bonelli M,Gadina M,et al.Type I/II cytokines,JAKs,and new strategies for treating autoimmune diseases[J].Nat Rev Rheumatol,2016,12(1):25-36.
[20]Flanagan M E,Blumenkopf T A,Brissette W H,et al.Discovery of CP-690,550:a potent and selective Janus kinase(JAK)inhibitor for the treatment of autoimmune diseases and organ transplant rejection[J].JMed Chem,2010,53(24):8468-8484.
[21]Arana Y C,Tam C S,Verstovsek S.Efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis[J].Future Oncol,2015,11(5):719-733.
[22]McKeage K.Ruxolitinib:a review in polycythaemia vera[J].Drugs,2015,75(15):1773-1781.
[23]Plosker G L.Ruxolitinib:a review of its use in patients with myelofibrosis[J].Drugs,2015,75(3):297-308.
[24]Kubo S,Nakayamada S,Tanaka Y.Baricitinib for the treatment of rheumatoid arthritis[J].Expert Rev Clin Immunol,2016,12(9):911-919.
[25]Markham A.Baricitinib:first global approval[J].Drugs,2017,77(6):697-704.
[26]Gras J.Baricitinib:JAK inhibition for rheumatoid arthritis[J].Drugs Today(Barc),2016,52(10):543-550.
[27]Vazquez M L,Kaila N,Strohbach J W,et al.Identification of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide(PF-04965842):a selective JAK1 clinical candidate for the treatment of autoimmune diseases[J].J Med Chem,2018,61(3):1130-1152.
[28]Hart S,Goh K C,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.
[29]William A D,Lee A C,Blanchard S,et al.Discovery of the macrocycle11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene(SB1518),a potent Janus kinase 2/fms-like tyrosine kinase-3(JAK2/FLT3)inhibitor for the treatment of myelofibrosis and lymphoma[J].JMed Chem,2011,54(13):4638-4658.
[30]Komrokji R S,Seymour J F,Roberts A W,et al.Results of a phase2 study of pacritinib(SB1518),a JAK2/JAK2(V617F)inhibitor,in patients with myelofibrosis[J].Blood,2015,125(17):2649-2655.
[31]Verstovsek S,Odenike O,Singer J W,et al.Phase 1/2 study of pacritinib,a next generation JAK2/FLT3 inhibitor,in myelofibrosis or other myeloid malignancies[J/OL].J Hematol Oncol,2016,9(1):137[2018-03-30].https://link.springer.com/article/10.1186/s13045-016-0367-x.
[32]Pardanani A,Lasho T,Smith G,et al.CYT387,a selective JAK1/JAK2inhibitor:in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients[J].Leukemia,2009,23(8):1441-1445.
[33]Tyner J W,Bumm T G,Deininger J,et al.CYT387,a novel JAK2inhibitor,induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms[J].Blood,2010,115(25):5232-5240.
[34]Mesa R A,Kiladjian J J,Catalano J V,et al.SIMPLIFY-1:a phase IIIrandomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis[J].J Clin Oncol,2017,35(34):3844-3850.
[35]Harrison C N,Vannucchi A M,Platzbecker U,et al.Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib(SIMPLIFY 2):a randomised,open-label,phase3 trial[J].Lancet Haematol,2018,5(2):e73-e81.
[36]Kuroda J,Kodama A,Chinen Y,et al.NS-018,a selective JAK2inhibitor,preferentially inhibits CFU-GM colony formation by bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients[J].Leuk Res,2014,38(5):619-624.
[37]Verstovsek S,Talpaz M,Ritchie E,et al.A phase I,open-label,doseescalation,multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis[J].Leukemia,2017,31(2):393-402.
[38]Kulagowski J J,Blair W,Bull R J,et al.Identification of imidazopyrrolopyridines as novel and potent JAK1 inhibitors[J].J Med Chem,2012,55(12):5901-5921.
[39]Zak M,Mendonca R,Balazs M,et al.Discovery and optimization of C-2methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1inhibitors with selectivity over JAK2[J].J Med Chem,2012,55(13):6176-6193.
[40]Zak M,Hurley C A,Ward S I,et al.Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2[J].J Med Chem,2013,56(11):4764-4785.
[41]Labadie S,Dragovich P S,Barrett K,et al.Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2[J].Bioorg Med Chem Lett,2012,22(24):7627-7633.
[42]Hurley C A,Blair W S,Bull R J,et al.Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1[J].Bioorg Med Chem Lett,2013,23(12):3592-3598.
[43]Nakayamada S,Kubo S,Iwata S,et al.Recent progress in JAKinhibitors for the treatment of rheumatoid arthritis[J].BioDrugs,2016,30(5):407-419.
[44]Menet C J,Mammoliti O,Lopez-Ramos M.Progress toward JAK1-selective inhibitors[J].Future Med Chem,2015,7(2):203-235.
[45]Genovese M C,Smolen J S,Weinblatt M E,et al.Efficacy and safety of ABT-494,a selective JAK-1 inhibitor,in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate[J].Arthritis Rheumatol,2016,68(12):2857-2866.
[46]Kremer J M,Emery P,Camp H S,et al.A phase IIb study of ABT-494,a selective JAK-1 inhibitor,in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy[J].Arthritis Rheumatol,2016,68(12):2867-2877.
[47]Thorarensen A,Dowty M E,Banker M E,et al.Design of a Janus kinase 3(JAK3)specific ihibitor 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one(PF-06651600)allowing for the interrogation of JAK3 signaling in humans[J].J Med Chem,2017,60(5):1971-1993.
[48]Telliez J B,Dowty M E,Wang L,et al.Discovery of a JAK3-selective inhibitor:functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition[J].ACS Chem Biol,2016,11(12):3442-3451.
[49]Tan L,Akahane K,McNally R,et al.Development of selective covalent Janus kinase 3 inhibitors[J].J Med Chem,2015,58(16):6589-6606.
[50]Kempson J,Ovalle D,Guo J,et al.Discovery of highly potent,selective,covalent inhibitors of JAK3[J].Bioorg Med Chem Lett,2017,27(20):4622-4625.
[51]Van Rompaey L,Galien R,van der Aar E M,et al.Preclinical characterization of GLPG0634,a selective inhibitor of JAK1,for the treatment of inflammatory diseases[J].J Immunol,2013,191(7):3568-3577.
[52]Kavanaugh A,Kremer J,Ponce L,et al.Filgotinib(GLPG0634/GS-6034),an oral selective JAK1 inhibitor,is effective as monotherapy in patients with active rheumatoid arthritis:results from a randomised,dose-finding study(DARWIN 2)[J].Ann Rheum Dis,2017,76(6):1009-1019.
[53]Takeuchi T,Tanaka Y,Iwasaki M,et al.Efficacy and safety of the oral Janus kinase inhibitor peficitinib(ASP015K)monotherapy in patients with moderate to severe rheumatoid arthritis in Japan:a 12-week,randomised,double-blind,placebo-controlled phase IIb study[J].Ann Rheum Dis,2016,75(6):1057-1064.
[2]Senkevitch E,Durum S.The promise of Janus kinase inhibitors in the treatment of hematological malignancies[J/OL].Cytokine,2017,98:33-41[2018-03-30].https://www.sciencedirect.com/science/article/abs/pii/S104346661630552X.Doi:10.1016/j.cyto.2016.10.012.
[3]Winthrop K L The emerging safety profile of JAK inhibitors in rheumatic disease[J].Nat Rev Rheumatol,2017,13(4):234-243.
[4]Roskoski R Jr.Janus kinase(JAK)inhibitors in the treatment of inflammatory and neoplastic diseases[J/OL].Pharmacol Res,2016,111:784-803[2018-03-30].https://www.sciencedirect.com/science/article/abs/pii/S1043661816307137.Doi:10.1016/j.phrs.2016.07.038.
[5]Babon J J,Lucet I S,Murphy J M,et al.The molecular regulation of Janus kinase(JAK)activation[J].Biochem J,2014,462(1):1-13.
[6]Wu W,Sun X H.Janus kinase 3:the controller and the controlled[J].Acta Biochim Biophys Sin(Shanghai),2012,44(3):187-196.
[7]Radtke S,Haan S,Jorissen A,et al.The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression[J].J Biol Chem,2005,280(27):25760-25768.
[8]Cai B,Cai J P,Luo Y L,et al.The specific roles of JAK/STAT signaling pathway in sepsis[J].Inflammation,2015,38(4):1599-1608.
[9]Scott L M,Gandhi M K.Deregulated JAK/STAT signalling in lymphomagenesis,and its implications for the development of new targeted therapies[J].Blood Rev,2015,29(6):405-415.
[10]Flamant M,Rigaill J,Paul S,et al.Advances in the development of Janus kinase inhibitors in inflammatory bowel disease:future prospects[J].Drugs,2017,77(10):1057-1068.
[11]Bose P,Verstovsek S.JAK2 inhibitors for myeloproliferative neoplasms:what is next?[J].Blood,2017,130(2):115-125.
[12]Babon J J,Lucet I S,Murphy J M,et al.The molecular regulation of Janus kinase(JAK)activation[J].Biochemical Journal,2014,462(1):1-13.
[13]Sun H B.Mechanical loading,cartilage degradation,and arthritis[J].Ann N Y Acad Sci,2010,1211(1):37-50.
[14]Tanaka Y.Recent progress and perspective in JAK inhibitors for rheumatoid arthritis:from bench to bedside[J].J Biochem,2015,158(3):173-179.
[15]Mascarenhas J O,Cross N C,Mesa R A.The future of JAK inhibition in myelofibrosis and beyond[J].Blood Rev,2014,28(5):189-196.
[16]Aittomaki S,Pesu M.Therapeutic targeting of the JAK/STATpathway[J].Basic Clin Pharmacol Toxicol,2014,114(1):18-23.
[17]Schwartz D M,Kanno Y,Villarino A,et al.JAK inhibition as a therapeutic strategy for immune and inflammatory diseases[J].Nat Rev Drug Discov,2017,16(12):843-862.
[18]Damsky W,King B A.JAK inhibitors in dermatology:the promise of a new drug class[J].J Am Acad Dermatol,2017,76(4):736-744.
[19]Schwartz D M,Bonelli M,Gadina M,et al.Type I/II cytokines,JAKs,and new strategies for treating autoimmune diseases[J].Nat Rev Rheumatol,2016,12(1):25-36.
[20]Flanagan M E,Blumenkopf T A,Brissette W H,et al.Discovery of CP-690,550:a potent and selective Janus kinase(JAK)inhibitor for the treatment of autoimmune diseases and organ transplant rejection[J].JMed Chem,2010,53(24):8468-8484.
[21]Arana Y C,Tam C S,Verstovsek S.Efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis[J].Future Oncol,2015,11(5):719-733.
[22]McKeage K.Ruxolitinib:a review in polycythaemia vera[J].Drugs,2015,75(15):1773-1781.
[23]Plosker G L.Ruxolitinib:a review of its use in patients with myelofibrosis[J].Drugs,2015,75(3):297-308.
[24]Kubo S,Nakayamada S,Tanaka Y.Baricitinib for the treatment of rheumatoid arthritis[J].Expert Rev Clin Immunol,2016,12(9):911-919.
[25]Markham A.Baricitinib:first global approval[J].Drugs,2017,77(6):697-704.
[26]Gras J.Baricitinib:JAK inhibition for rheumatoid arthritis[J].Drugs Today(Barc),2016,52(10):543-550.
[27]Vazquez M L,Kaila N,Strohbach J W,et al.Identification of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide(PF-04965842):a selective JAK1 clinical candidate for the treatment of autoimmune diseases[J].J Med Chem,2018,61(3):1130-1152.
[28]Hart S,Goh K C,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.
[29]William A D,Lee A C,Blanchard S,et al.Discovery of the macrocycle11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene(SB1518),a potent Janus kinase 2/fms-like tyrosine kinase-3(JAK2/FLT3)inhibitor for the treatment of myelofibrosis and lymphoma[J].JMed Chem,2011,54(13):4638-4658.
[30]Komrokji R S,Seymour J F,Roberts A W,et al.Results of a phase2 study of pacritinib(SB1518),a JAK2/JAK2(V617F)inhibitor,in patients with myelofibrosis[J].Blood,2015,125(17):2649-2655.
[31]Verstovsek S,Odenike O,Singer J W,et al.Phase 1/2 study of pacritinib,a next generation JAK2/FLT3 inhibitor,in myelofibrosis or other myeloid malignancies[J/OL].J Hematol Oncol,2016,9(1):137[2018-03-30].https://link.springer.com/article/10.1186/s13045-016-0367-x.
[32]Pardanani A,Lasho T,Smith G,et al.CYT387,a selective JAK1/JAK2inhibitor:in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients[J].Leukemia,2009,23(8):1441-1445.
[33]Tyner J W,Bumm T G,Deininger J,et al.CYT387,a novel JAK2inhibitor,induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms[J].Blood,2010,115(25):5232-5240.
[34]Mesa R A,Kiladjian J J,Catalano J V,et al.SIMPLIFY-1:a phase IIIrandomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis[J].J Clin Oncol,2017,35(34):3844-3850.
[35]Harrison C N,Vannucchi A M,Platzbecker U,et al.Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib(SIMPLIFY 2):a randomised,open-label,phase3 trial[J].Lancet Haematol,2018,5(2):e73-e81.
[36]Kuroda J,Kodama A,Chinen Y,et al.NS-018,a selective JAK2inhibitor,preferentially inhibits CFU-GM colony formation by bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients[J].Leuk Res,2014,38(5):619-624.
[37]Verstovsek S,Talpaz M,Ritchie E,et al.A phase I,open-label,doseescalation,multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis[J].Leukemia,2017,31(2):393-402.
[38]Kulagowski J J,Blair W,Bull R J,et al.Identification of imidazopyrrolopyridines as novel and potent JAK1 inhibitors[J].J Med Chem,2012,55(12):5901-5921.
[39]Zak M,Mendonca R,Balazs M,et al.Discovery and optimization of C-2methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1inhibitors with selectivity over JAK2[J].J Med Chem,2012,55(13):6176-6193.
[40]Zak M,Hurley C A,Ward S I,et al.Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2[J].J Med Chem,2013,56(11):4764-4785.
[41]Labadie S,Dragovich P S,Barrett K,et al.Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2[J].Bioorg Med Chem Lett,2012,22(24):7627-7633.
[42]Hurley C A,Blair W S,Bull R J,et al.Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1[J].Bioorg Med Chem Lett,2013,23(12):3592-3598.
[43]Nakayamada S,Kubo S,Iwata S,et al.Recent progress in JAKinhibitors for the treatment of rheumatoid arthritis[J].BioDrugs,2016,30(5):407-419.
[44]Menet C J,Mammoliti O,Lopez-Ramos M.Progress toward JAK1-selective inhibitors[J].Future Med Chem,2015,7(2):203-235.
[45]Genovese M C,Smolen J S,Weinblatt M E,et al.Efficacy and safety of ABT-494,a selective JAK-1 inhibitor,in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate[J].Arthritis Rheumatol,2016,68(12):2857-2866.
[46]Kremer J M,Emery P,Camp H S,et al.A phase IIb study of ABT-494,a selective JAK-1 inhibitor,in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy[J].Arthritis Rheumatol,2016,68(12):2867-2877.
[47]Thorarensen A,Dowty M E,Banker M E,et al.Design of a Janus kinase 3(JAK3)specific ihibitor 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one(PF-06651600)allowing for the interrogation of JAK3 signaling in humans[J].J Med Chem,2017,60(5):1971-1993.
[48]Telliez J B,Dowty M E,Wang L,et al.Discovery of a JAK3-selective inhibitor:functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition[J].ACS Chem Biol,2016,11(12):3442-3451.
[49]Tan L,Akahane K,McNally R,et al.Development of selective covalent Janus kinase 3 inhibitors[J].J Med Chem,2015,58(16):6589-6606.
[50]Kempson J,Ovalle D,Guo J,et al.Discovery of highly potent,selective,covalent inhibitors of JAK3[J].Bioorg Med Chem Lett,2017,27(20):4622-4625.
[51]Van Rompaey L,Galien R,van der Aar E M,et al.Preclinical characterization of GLPG0634,a selective inhibitor of JAK1,for the treatment of inflammatory diseases[J].J Immunol,2013,191(7):3568-3577.
[52]Kavanaugh A,Kremer J,Ponce L,et al.Filgotinib(GLPG0634/GS-6034),an oral selective JAK1 inhibitor,is effective as monotherapy in patients with active rheumatoid arthritis:results from a randomised,dose-finding study(DARWIN 2)[J].Ann Rheum Dis,2017,76(6):1009-1019.
[53]Takeuchi T,Tanaka Y,Iwasaki M,et al.Efficacy and safety of the oral Janus kinase inhibitor peficitinib(ASP015K)monotherapy in patients with moderate to severe rheumatoid arthritis in Japan:a 12-week,randomised,double-blind,placebo-controlled phase IIb study[J].Ann Rheum Dis,2016,75(6):1057-1064.