Target General Infomation
Target ID
T08391
Former ID
TTDC00187
Target Name
Tyrosine-protein kinase JAK2
Gene Name
JAK2
Synonyms
JAK-2; Janus kinase 2; JAK2
Target Type
Clinical Trial
Disease Anemia [ICD9: 280-285; ICD10: D50-D64]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Essential thrombocythemia [ICD9: 238.71, 289.9; ICD10: D47.3, D75.2, D75.8]
Leukemia [ICD9: 208.9; ICD10: C90-C95]
Myelofibrosis [ICD9: 208.9, 289.83, 709.2; ICD10: C94.4, D47.4]
Myelofibrosis; Essential thrombocythemia; Polycythemia vera [ICD9: 238.71, 289.0, 289.83, 289.9, 776.4; ICD10: C94.4, D47.1, D47.3, D75.1, D75.2, D75.8, P61.1]
Myeloproliferative disorder [ICD10: C94.6]
Multiple scierosis [ICD9: 340; ICD10: G35]
Malignancies [ICD9: 140-239; ICD10: C00-C96]
Myeloproliferative neoplasm; Breast cancer [ICD9:205.1, 238.4, 289.89, 289.9, 174, 175; ICD10: D47.1, C50]
Non-hodgkin's lymphoma [ICD10: C85]
Polycythemia vera [ICD9: 238.4; ICD10: D45]
Pancreatic cancer [ICD9: 140-199, 140-229, 157, 210-229; ICD10: C25]
Renal transplantation; Multiple myeloma [ICD9:279.5, 203; ICD10: D89.8, C90]
Rheumatold arthritis; Psoriasis; Diabetic nephropathy [ICD9: 250, 250.4, 580-599, 696, 710-719, 714; ICD10: E08-E13, E10.2, E11.2, E13.2, L40, M00-M25, M05-M06, N00-N29]
Function
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated,dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In thenucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.
BioChemical Class
Kinase
Target Validation
T08391
UniProt ID
EC Number
EC 2.7.10.2
Sequence
MGMACLTMTEMEGTSTSSIYQNGDISGNANSMKQIDPVLQVYLYHSLGKSEADYLTFPSG
EYVAEEICIAASKACGITPVYHNMFALMSETERIWYPPNHVFHIDESTRHNVLYRIRFYF
PRWYCSGSNRAYRHGISRGAEAPLLDDFVMSYLFAQWRHDFVHGWIKVPVTHETQEECLG
MAVLDMMRIAKENDQTPLAIYNSISYKTFLPKCIRAKIQDYHILTRKRIRYRFRRFIQQF
SQCKATARNLKLKYLINLETLQSAFYTEKFEVKEPGSGPSGEEIFATIIITGNGGIQWSR
GKHKESETLTEQDLQLYCDFPNIIDVSIKQANQEGSNESRVVTIHKQDGKNLEIELSSLR
EALSFVSLIDGYYRLTADAHHYLCKEVAPPAVLENIQSNCHGPISMDFAISKLKKAGNQT
GLYVLRCSPKDFNKYFLTFAVERENVIEYKHCLITKNENEEYNLSGTKKNFSSLKDLLNC
YQMETVRSDNIIFQFTKCCPPKPKDKSNLLVFRTNGVSDVPTSPTLQRPTHMNQMVFHKI
RNEDLIFNESLGQGTFTKIFKGVRREVGDYGQLHETEVLLKVLDKAHRNYSESFFEAASM
MSKLSHKHLVLNYGVCVCGDENILVQEFVKFGSLDTYLKKNKNCINILWKLEVAKQLAWA
MHFLEENTLIHGNVCAKNILLIREEDRKTGNPPFIKLSDPGISITVLPKDILQERIPWVP
PECIENPKNLNLATDKWSFGTTLWEICSGGDKPLSALDSQRKLQFYEDRHQLPAPKWAEL
ANLINNCMDYEPDFRPSFRAIIRDLNSLFTPDYELLTENDMLPNMRIGALGFSGAFEDRD
PTQFEERHLKFLQQLGKGNFGSVEMCRYDPLQDNTGEVVAVKKLQHSTEEHLRDFEREIE
ILKSLQHDNIVKYKGVCYSAGRRNLKLIMEYLPYGSLRDYLQKHKERIDHIKLLQYTSQI
CKGMEYLGTKRYIHRDLATRNILVENENRVKIGDFGLTKVLPQDKEYYKVKEPGESPIFW
YAPESLTESKFSVASDVWSFGVVLYELFTYIEKSKSPPAEFMRMIGNDKQGQMIVFHLIE
LLKNNGRLPRPDGCPDEIYMIMTECWNNNVNQRPSFRDLALRVDQIRDNMAG
Drugs and Mode of Action
Drug(s) Ruxolitinib Drug Info Phase 4 Essential thrombocythemia [523729], [541031]
Baricitinib Drug Info Phase 3 Rheumatold arthritis; Psoriasis; Diabetic nephropathy [524953], [542743]
Momelotinib Drug Info Phase 3 Myelofibrosis [524489], [542742]
Pacritinib Drug Info Phase 3 Myelofibrosis [524636], [542744], [550572]
Ruxolitinib Drug Info Phase 3 Pancreatic cancer [524723], [541031]
XL019 Drug Info Phase 3 Cancer [532295], [542887]
AZD1480 Drug Info Phase 2 Myeloproliferative disorder [532522], [541219]
BMS-911543 Drug Info Phase 2 Myelofibrosis [531666], [542870]
INCB039110 Drug Info Phase 2 Malignancies [543090]
ITF2357 Drug Info Phase 2 Myelofibrosis; Essential thrombocythemia; Polycythemia vera [537520], [542513]
LY2784544 Drug Info Phase 2 Myeloproliferative neoplasm; Breast cancer [523899], [542831], [549758]
Ruxolitinib Drug Info Approved High-risk myelofibrosis [524601], [533122], [541031], [556264]
Cerdulatinib Drug Info Phase 1/2 Non-hodgkin's lymphoma [551978]
NS-018 Drug Info Phase 1/2 Myelofibrosis [532622], [542781]
TG101348 Drug Info Phase 1/2 Myelofibrosis [537520]
AC430 Drug Info Phase 1 Leukemia [523342]
Peginterferon beta Drug Info Phase 1 Multiple scierosis [549138]
SB-1578 Drug Info Phase 1 Cancer [523243]
XL019 Drug Info Phase 1 Polycythemia vera [537520], [542887]
AG490 Drug Info Terminated Renal transplantation; Multiple myeloma [541206], [546151]
Inhibitor 5-phenyl-1H-indazol-3-amine Drug Info [551374]
AG490 Drug Info [535970]
AMG-JAK2-01 Drug Info [543545]
Atropisomer 1 Drug Info [530583]
AZ960 Drug Info [529674]
BVB-808 Drug Info [543545]
CMP-6 Drug Info [526307]
compound 19a Drug Info [532598]
compound 1d Drug Info [531435]
EPO program, Medexgen Drug Info [543545]
INCB039110 Drug Info [543545]
ITF2357 Drug Info [537114], [537520]
Jak2 inhibitors Drug Info [543545]
Jak2 tyrosine inhibitors Drug Info [543545]
K-454 Drug Info [543545]
NSC-1771 Drug Info [531262]
ON-044580 Drug Info [531107]
Peginterferon beta Drug Info [529516]
SB-1578 Drug Info [532038], [532777]
SGI-1252 Drug Info [543545]
TG101348 Drug Info [531331], [537520]
Tyrphostin AG490 Drug Info [535289]
WHI-P154 Drug Info [529228]
XL019 Drug Info [537520]
Modulator AC430 Drug Info [532777]
AZD1480 Drug Info [530557]
Baricitinib Drug Info [532777]
BMS-911543 Drug Info [531666]
Cerdulatinib Drug Info
LY2784544 Drug Info [532307]
Momelotinib Drug Info
NS-018 Drug Info [532622]
Pacritinib Drug Info [550433]
Ruxolitinib Drug Info [531783]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Chemokine signaling pathway
PI3K-Akt signaling pathway
Signaling pathways regulating pluripotency of stem cells
Jak-STAT signaling pathway
Cholinergic synapse
Prolactin signaling pathway
Adipocytokine signaling pathway
Leishmaniasis
Toxoplasmosis
Tuberculosis
Measles
Influenza A
Herpes simplex infection
PANTHER Pathway Inflammation mediated by chemokine and cytokine signaling pathway
Interferon-gamma signaling pathway
JAK/STAT signaling pathway
PDGF signaling pathway
PI3 kinase pathway
CCKR signaling map ST
Pathway Interaction Database Endothelins
ErbB4 signaling events
GMCSF-mediated signaling events
IL4-mediated signaling events
IL27-mediated signaling events
Signaling events mediated by PTP1B
IL12-mediated signaling events
S1P3 pathway
SHP2 signaling
CXCR4-mediated signaling events
IL5-mediated signaling events
IFN-gamma pathway
ErbB2/ErbB3 signaling events
IL3-mediated signaling events
IL6-mediated signaling events
PDGFR-beta signaling pathway
IL23-mediated signaling events
Signaling events mediated by Stem cell factor receptor (c-Kit)
EPO signaling pathway
Notch-mediated HES/HEY network
Reactome Interleukin-6 signaling
MAPK3 (ERK1) activation
MAPK1 (ERK2) activation
GPVI-mediated activation cascade
Prolactin receptor signaling
RMTs methylate histone arginines
gamma signalling through PI3Kgamma
Interleukin-3, 5 and GM-CSF signaling
RAF activation
RAF/MAP kinase cascade
Interferon gamma signaling
Regulation of IFNG signaling
Interleukin receptor SHC signaling
Growth hormone receptor signaling
Factors involved in megakaryocyte development and platelet production
WikiPathways Serotonin Receptor 2 and STAT3 Signaling
Type II interferon signaling (IFNG)
Notch Signaling Pathway
EPO Receptor Signaling
EGF/EGFR Signaling Pathway
IL-4 Signaling Pathway
IL-6 signaling pathway
Kit receptor signaling pathway
IL-3 Signaling Pathway
Mesodermal Commitment Pathway
Interleukin-2 signaling
Signaling by SCF-KIT
Prolactin receptor signaling
Growth hormone receptor signaling
JAK/STAT
BDNF signaling pathway
Oncostatin M Signaling Pathway
Interleukin-11 Signaling Pathway
AGE/RAGE pathway
TSLP Signaling Pathway
IL17 signaling pathway
Leptin signaling pathway
TSH signaling pathway
Interleukin-3, 5 and GM-CSF signaling
Interferon gamma signaling
Factors involved in megakaryocyte development and platelet production
IL-5 Signaling Pathway
References
Ref 523243ClinicalTrials.gov (NCT01235871) A Single and Multiple-Dose Study of SB1578. U.S. National Institutes of Health.
Ref 523342ClinicalTrials.gov (NCT01287858) Study to Assess Safety, Tolerability, and Pharmacokinetics of Oral Doses for AC430 in Healthy Subjects. U.S. National Institutes of Health.
Ref 523729ClinicalTrials.gov (NCT01493414) INC424 for Patients With Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis. U.S. National Institutes of Health.
Ref 523899ClinicalTrials.gov (NCT01594723) A Study of LY2784544 in Participants With Myeloproliferative Neoplasms. U.S. National Institutes of Health.
Ref 524489ClinicalTrials.gov (NCT01969838) Momelotinib Versus Ruxolitinib in Subjects With Myelofibrosis. U.S. National Institutes of Health.
Ref 524601ClinicalTrials.gov (NCT02038036) Ruxolitinib Efficacy and Safety in Patients With HU Resistant or Intolerant Polycythemia Vera vs Best Available Therapy.. U.S. National Institutes of Health.
Ref 524636ClinicalTrials.gov (NCT02055781) Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis With Thrombocytopenia. U.S. National Institutes of Health.
Ref 524723ClinicalTrials.gov (NCT02117479) Study of Ruxolitinib in Pancreatic Cancer Patients (Janus 1). U.S. National Institutes of Health.
Ref 524953ClinicalTrials.gov (NCT02265705) A Study of Baricitinib (LY3009104) in Participants With Rheumatoid Arthritis (RA). U.S. National Institutes of Health.
Ref 531666Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8.
Ref 532295Update on JAK2 Inhibitors in Myeloproliferative Neoplasm. Ther Adv Hematol. 2011 Apr;2(2):61-71.
Ref 532522The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo. Clin Cancer Res. 2013 Dec 15;19(24):6777-86.
Ref 532622Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis. Blood Cancer J. 2014 Jan 10;4:e174.
Ref 533122Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015 Jan 29;372(5):426-35.
Ref 537520Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. Expert Opin Emerg Drugs. 2009 Jun 24.
Ref 541031(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5688).
Ref 541206(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5916).
Ref 541219(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5933).
Ref 542513(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7490).
Ref 542742(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7791).
Ref 542743(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7792).
Ref 542744(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7793).
Ref 542781(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7839).
Ref 542831(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7909).
Ref 542870(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7954).
Ref 542887(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7971).
Ref 543090(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8364).
Ref 546151Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006610)
Ref 549138Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032732)
Ref 549758LY2784544, a small molecule JAK2 inhibitor, induces apoptosis in inflammatory breast cancer spheres through targeting IL-6-JAK-STAT3 pathway. Cancer Research 07/2011; 71(8 Supplement):2820-2820.
Ref 550572Clinical pipeline report, company report or official report of CTI BioPharma.
Ref 551978Clinical pipeline report, company report or official report of Portola.
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
Ref 526307Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23.
Ref 529228The specificity of JAK3 kinase inhibitors. Blood. 2008 Feb 15;111(4):2155-7. Epub 2007 Dec 19.
Ref 529516Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders. Leukemia. 2008 Jul;22(7):1320-34.
Ref 529674Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2. J Biol Chem. 2008 Nov 21;283(47):32334-43.
Ref 530557The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009 Dec 8;16(6):487-97.
Ref 530583J Med Chem. 2009 Dec 24;52(24):7938-41.Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole.
Ref 531107A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition. Genes Cancer. 2010 Apr;1(4):331-45.
Ref 531262Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6. Epub 2010 Oct 21.In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2).
Ref 531331Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011 Mar 1;29(7):789-96.
Ref 531435In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61.
Ref 531666Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8.
Ref 5317832011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
Ref 532038SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis. J Immunol. 2012 Oct 15;189(8):4123-34.
Ref 532307Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013 Apr 12;3:e109.
Ref 532598Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors. J Med Chem. 2014 Jan 9;57(1):144-58.
Ref 532622Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis. Blood Cancer J. 2014 Jan 10;4:e174.
Ref 532777Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs. 2014 Aug;23(8):1067-77.
Ref 535289The JAK2 inhibitor AG490 predominantly abrogates the growth of human B-precursor leukemic cells with 11q23 translocation or Philadelphia chromosome. Leukemia. 2001 Nov;15(11):1758-68.
Ref 535970Jak2 tyrosine kinase mediates oxidative stress-induced apoptosis in vascular smooth muscle cells. J Biol Chem. 2004 Aug 13;279(33):34547-52. Epub 2004 May 24.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 537520Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. Expert Opin Emerg Drugs. 2009 Jun 24.
Ref 543545(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2048).
Ref 550433National Cancer Institute Drug Dictionary (drug id 609888).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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