Target Information
Target General Infomation | |||||
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Target ID |
T23172
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Former ID |
TTDC00084
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Target Name |
Tyrosine-protein kinase JAK3
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Gene Name |
JAK3
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Synonyms |
JAK-3; Janus kinase 3; L-JAK; Leukocyte janus kinase; JAK3
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Target Type |
Successful
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Disease | Autoimmune diabetes [ICD10: E08-E13] | ||||
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25] | |||||
Psoriasis [ICD9: 696; ICD10: L40] | |||||
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06] | |||||
Renal transplantation [ICD9: 279.5; ICD10: D89.8] | |||||
Renal transplantation; Multiple myeloma [ICD9:279.5, 203; ICD10: D89.8, C90] | |||||
Function |
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R,IL9R, IL15R and IL21R. 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, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunitson their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.
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BioChemical Class |
Kinase
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Target Validation |
T23172
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UniProt ID | |||||
EC Number |
EC 2.7.10.2
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Sequence |
MAPPSEETPLIPQRSCSLLSTEAGALHVLLPARGPGPPQRLSFSFGDHLAEDLCVQAAKA
SGILPVYHSLFALATEDLSCWFPPSHIFSVEDASTQVLLYRIRFYFPNWFGLEKCHRFGL RKDLASAILDLPVLEHLFAQHRSDLVSGRLPVGLSLKEQGECLSLAVLDLARMAREQAQR PGELLKTVSYKACLPPSLRDLIQGLSFVTRRRIRRTVRRALRRVAACQADRHSLMAKYIM DLERLDPAGAAETFHVGLPGALGGHDGLGLLRVAGDGGIAWTQGEQEVLQPFCDFPEIVD ISIKQAPRVGPAGEHRLVTVTRTDNQILEAEFPGLPEALSFVALVDGYFRLTTDSQHFFC KEVAPPRLLEEVAEQCHGPITLDFAINKLKTGGSRPGSYVLRRSPQDFDSFLLTVCVQNP LGPDYKGCLIRRSPTGTFLLVGLSRPHSSLRELLATCWDGGLHVDGVAVTLTSCCIPRPK EKSNLIVVQRGHSPPTSSLVQPQSQYQLSQMTFHKIPADSLEWHENLGHGSFTKIYRGCR HEVVDGEARKTEVLLKVMDAKHKNCMESFLEAASLMSQVSYRHLVLLHGVCMAGDSTMVQ EFVHLGAIDMYLRKRGHLVPASWKLQVVKQLAYALNYLEDKGLPHGNVSARKVLLAREGA DGSPPFIKLSDPGVSPAVLSLEMLTDRIPWVAPECLREAQTLSLEADKWGFGATVWEVFS GVTMPISALDPAKKLQFYEDRQQLPAPKWTELALLIQQCMAYEPVQRPSFRAVIRDLNSL ISSDYELLSDPTPGALAPRDGLWNGAQLYACQDPTIFEERHLKYISQLGKGNFGSVELCR YDPLGDNTGALVAVKQLQHSGPDQQRDFQREIQILKALHSDFIVKYRGVSYGPGRQSLRL VMEYLPSGCLRDFLQRHRARLDASRLLLYSSQICKGMEYLGSRRCVHRDLAARNILVESE AHVKIADFGLAKLLPLDKDYYVVREPGQSPIFWYAPESLSDNIFSRQSDVWSFGVVLYEL FTYCDKSCSPSAEFLRMMGCERDVPALCRLLELLEEGQRLPAPPACPAEVHELMKLCWAP SPQDRPSFSALGPQLDMLWSGSRGCETHAFTAHPEGKHHSLSFS |
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Structure |
1YVJ; 3LXK; 3LXL; 3PJC; 3ZC6; 3ZEP; 4HVD; 4HVG; 4HVH; 4HVI; 4I6Q; 4QPS; 4RIO
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Drugs and Mode of Action | |||||
Drug(s) | Tofacitinib | Drug Info | Approved | Rheumatoid arthritis | [1], [2], [3] |
ASP-015K | Drug Info | Phase 3 | Psoriasis | [4], [5] | |
VX-509 | Drug Info | Phase 2/3 | Rheumatoid arthritis | [6], [7] | |
AG490 | Drug Info | Terminated | Renal transplantation; Multiple myeloma | [8], [9] | |
PNU156804 | Drug Info | Terminated | Renal transplantation | [10] | |
R348 | Drug Info | Terminated | Psoriasis | [11] | |
Inhibitor | 6-o-tolylquinazolin-2-amine | Drug Info | [12] | ||
AD-412 | Drug Info | [13] | |||
AG490 | Drug Info | [14] | |||
ASP-015K | Drug Info | [13] | |||
Atropisomer 1 | Drug Info | [15] | |||
CMP-6 | Drug Info | [16] | |||
compound 19a | Drug Info | [17] | |||
compound 1d | Drug Info | [18] | |||
compound 2 | Drug Info | [19] | |||
NC1153 | Drug Info | [14] | |||
PF-956980 | Drug Info | [13] | |||
PNU156804 | Drug Info | [20] | |||
R348 | Drug Info | [11] | |||
VX-467 | Drug Info | [13] | |||
VX-509 | Drug Info | [21], [22] | |||
WHI-P154 | Drug Info | [23] | |||
ZM-39923 | Drug Info | [24] | |||
Modulator | Tofacitinib | Drug Info | [3] | ||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | Chemokine signaling pathway | ||||
PI3K-Akt signaling pathway | |||||
Signaling pathways regulating pluripotency of stem cells | |||||
Jak-STAT signaling pathway | |||||
Measles | |||||
HTLV-I infection | |||||
Epstein-Barr virus infection | |||||
Viral carcinogenesis | |||||
Primary immunodeficiency | |||||
PANTHER Pathway | Interleukin signaling pathway | ||||
JAK/STAT signaling pathway | |||||
PDGF signaling pathway | |||||
Pathway Interaction Database | IL4-mediated signaling events | ||||
CD40/CD40L signaling | |||||
Signaling events mediated by TCPTP | |||||
SHP2 signaling | |||||
IL2-mediated signaling events | |||||
IL2 signaling events mediated by PI3K | |||||
IL2 signaling events mediated by STAT5 | |||||
Reactome | GPVI-mediated activation cascade | ||||
Interleukin-7 signaling | |||||
gamma signalling through PI3Kgamma | |||||
Interleukin-2 signaling | |||||
RAF/MAP kinase cascade | |||||
Interleukin receptor SHC signaling | |||||
WikiPathways | IL-2 Signaling Pathway | ||||
IL-4 Signaling Pathway | |||||
Interleukin-2 signaling | |||||
Interleukin-7 signaling | |||||
Oncostatin M Signaling Pathway | |||||
IL-9 Signaling Pathway | |||||
IL-7 Signaling Pathway | |||||
Interleukin-3, 5 and GM-CSF signaling | |||||
References | |||||
REF 1 | ClinicalTrials.gov (NCT02157012) Evaluation of the Condition of Rheumatoid Arthritis After Treatment. U.S. National Institutes of Health. | ||||
REF 2 | (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: 5677). | ||||
REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | ||||
REF 4 | ClinicalTrials.gov (NCT02308163) A Study to Evaluate Safety and Efficacy of ASP015K in Patients With Rheumatoid Arthritis (RA) Who Had an Inadequate Response to DMARDs. U.S. National Institutes of Health. | ||||
REF 5 | (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: 8315). | ||||
REF 6 | ClinicalTrials.gov (NCT01830985) A Phase 2/3 Open-label Extension Study to Evaluate Long-Term Safety and Efficacy With VX-509 in Subjects With Rheumatoid Arthritis. U.S. National Institutes of Health. | ||||
REF 7 | (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: 8309). | ||||
REF 8 | (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 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006610) | ||||
REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008393) | ||||
REF 11 | Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63. | ||||
REF 12 | J Med Chem. 2006 Sep 21;49(19):5671-86.Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity. | ||||
REF 13 | (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: 2049). | ||||
REF 14 | Immunotherapy for De Novo renal transplantation: what's in the pipeline? Drugs. 2006;66(13):1665-84. | ||||
REF 15 | J Med Chem. 2009 Dec 24;52(24):7938-41.Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole. | ||||
REF 16 | Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. | ||||
REF 17 | Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors. J Med Chem. 2014 Jan 9;57(1):144-58. | ||||
REF 18 | In 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 19 | Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg Med Chem Lett. 2004 Dec 20;14(24):6061-6. | ||||
REF 20 | Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. Blood. 2002 Jan 15;99(2):680-9. | ||||
REF 21 | Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs. 2014 Aug;23(8):1067-77. | ||||
REF 22 | VX-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. J Pharmacol Exp Ther. 2015 May;353(2):405-14. | ||||
REF 23 | The specificity of JAK3 kinase inhibitors. Blood. 2008 Feb 15;111(4):2155-7. Epub 2007 Dec 19. | ||||
REF 24 | Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett. 2000 Mar 20;10(6):575-9. |
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