Janus kinase (JakA) family | Enzymes | IUPHAR/BPS Guide to PHARMACOLOGY

Janus kinase (JakA) family C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). They are essential for cytokine signalling and are strongly linked to both cancer and inflammatory diseases.

Enzymes

JAK1 (Janus kinase 1) C Show summary »« Hide summary More detailed page

JAK2 (Janus kinase 2) C Show summary »« Hide summary More detailed page

Target Id

2048

Nomenclature

Janus kinase 2

Common abbreviation

JAK2

Previous and unofficial names

JTK10

Genes

JAK2 (Hs), Jak2 (Mm), Jak2 (Rn)

Ensembl ID

ENSG00000096968 (Hs), ENSMUSG00000024789 (Mm), ENSRNOG00000015547 (Rn)

UniProtKB AC

O60674 (Hs), Q62120 (Mm), Q62689 (Rn)

EC number

2.7.10.2

Inhibitors

ilginatinib pIC₅₀ 9.1 [8]

BMS-911543 pIC₅₀ 9.0 [9]

AT-9283 pIC₅₀ 8.9 [5]

XL019 pIC₅₀ 8.7 [3]

fedratinib pIC₅₀ 8.5 [7,13]

gandotinib pIC₅₀ 8.4 [6]

Selective inhibitors

compound 1d [PMID: 21493067] pIC₅₀ >9.0 [12]

Comment

The JAK2^V617F mutation, which causes constitutive activation, plays an oncogenic role in the pathogenesis of the myeloproliferative disorders, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis [1-2]. Small molecule compounds which inhibit aberrant JAK2 activity are being developed as novel anti-cancer pharmaceuticals.

JAK3 (Janus kinase 3) C Show summary »« Hide summary More detailed page

Tyk2 (tyrosine kinase 2) C Show summary »« Hide summary More detailed page

References

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1. Campbell PJ, Green AR. (2006) The myeloproliferative disorders. N. Engl. J. Med., 355 (23): 2452-66. [PMID:17151367]

2. Delhommeau F, Pisani DF, James C, Casadevall N, Constantinescu S, Vainchenker W. (2006) Oncogenic mechanisms in myeloproliferative disorders. Cell. Mol. Life Sci., 63 (24): 2939-53. [PMID:17131059]

3. Forsyth T, Kearney PC, Kim BG, Johnson HW, Aay N, Arcalas A, Brown DS, Chan V, Chen J, Du H et al.. (2012) SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg. Med. Chem. Lett., 22 (24): 7653-8. [PMID:23127890]

4. Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA et al.. (2012) Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors. J. Med. Chem., 55 (22): 10090-107. [PMID:23061660]

5. Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL et al.. (2009) Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J. Med. Chem., 52 (2): 379-88. [PMID:19143567]

6. Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith MC, Heinz-Taheny KM, Kreklau EL, Bloem L, Pitou C et al.. (2013) Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J, 3: e109. [PMID:23584399]

7. Malerich JP, Lam JS, Hart B, Fine RM, Klebansky B, Tanga MJ, D'Andrea A. (2010) Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3. Bioorg. Med. Chem. Lett., 20 (24): 7454-7. [PMID:21106455]

8. Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, Kuramoto K, Kotera T, Shibayama H, Hori K et al.. (2011) Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood Cancer J, 1 (7): e29. [PMID:22829185]

9. Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL et al.. (2012) Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia., 26 (2): 280-8. [PMID:22015772]

10. Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P et al.. (2010) Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 115 (15): 3109-17. [PMID:20130243]

11. Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, Lepescheux L, Christophe T, Conrath K, Vandeghinste N et al.. (2013) Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J. Immunol., 191 (7): 3568-77. [PMID:24006460]

12. Wang T, Ioannidis S, Almeida L, Block MH, Davies AM, Lamb ML, Scott DA, Su M, Zhang HJ, Alimzhanov M et al.. (2011) In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg. Med. Chem. Lett., 21 (10): 2958-61. [PMID:21493067]

13. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, Gozo M, McDowell EP, Levine RL, Doukas J et al.. (2008) Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell, 13 (4): 311-20. [PMID:18394554]

How to cite this family page

Database page citation:

Janus kinase (JakA) family. Accessed on 24/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=581.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. Br J Pharmacol. 174 Suppl 1: S272-S359.