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Janus kinase 3

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Target id: 2049

Nomenclature: Janus kinase 3

Abbreviated Name: JAK3

Family: Janus kinase (JakA) family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1124 19p13.11 JAK3 Janus kinase 3
Mouse - 1100 8 34.43 cM Jak3 Janus kinase 3
Rat - 1100 16p14 Jak3 Janus kinase 3
Previous and Unofficial Names Click here for help
JAKL | leukocyte Janus kinase | LJAK
Database Links Click here for help
Alphafold P52333 (Hs), Q62137 (Mm), Q63272 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 3.30.505.10, 1.20.80.10
ChEMBL Target CHEMBL2148 (Hs), CHEMBL5250 (Mm), CHEMBL4295857 (Rn)
DrugBank Target P52333 (Hs)
Ensembl Gene ENSG00000105639 (Hs), ENSMUSG00000031805 (Mm), ENSRNOG00000018669 (Rn)
Entrez Gene 3718 (Hs), 16453 (Mm), 25326 (Rn)
Human Protein Atlas ENSG00000105639 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:3718 (Hs), mmu:16453 (Mm), rno:25326 (Rn)
OMIM 600173 (Hs)
Orphanet ORPHA122729 (Hs)
Pharos P52333 (Hs)
RefSeq Nucleotide NM_000215 (Hs), NM_001190830 (Mm), NM_012855 (Rn)
RefSeq Protein NP_000206 (Hs), NP_001177759 (Mm), NP_036987 (Rn)
SynPHARM 80437 (in complex with JAK inhibitor I)
85283 (in complex with tofacitinib)
UniProtKB P52333 (Hs), Q62137 (Mm), Q63272 (Rn)
Wikipedia JAK3 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  JAK3 kinase domain in complex with 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide
PDB Id:  4HVD
Resolution:  1.85Å
Species:  Human
References:  47
Image of receptor 3D structure from RCSB PDB
Description:  JAK3 with Cyanamide CP34.
PDB Id:  6DB4
Ligand:  JAK3 inhibitor 34
Resolution:  1.7Å
Species:  Human
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of JAK3 in complex with delgocitinib
PDB Id:  7C3N
Ligand:  delgocitinib
Resolution:  1.98Å
Species:  Human
References:  41
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
nezulcitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 10.2 pKi 37
⤷ pKi 10.2 (Ki 6.3x10-11 M) [37]
delgocitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pKi 50
⤷ pKi 8.3 (Ki 5.5x10-9 M) [50]
Description: In an assay using the kinase domain of the recombinant human enzyme, a biotinylated peptide substrate, and [33P]ATP.
izencitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 – 9.0 pKi 31
⤷ pKi 7.0 – 9.0 (Ki 1x10-7 – 1x10-9 M) [31]
GDC-0214 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.7 pKi 20
⤷ pKi 7.7 (Ki 2.08x10-8 M) [20]
abivertinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 10.1 pIC50 59
⤷ pIC50 10.1 (IC50 9x10-11 M) [59]
Description: In a biochemical assay.
ritlecitinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.5 pIC50
⤷ pIC50 9.5 (IC50 3x10-10 M)
Description: At 4 μM ATP (Km).
AT-9283 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.0 pIC50 30
⤷ pIC50 9.0 (IC50 1.1x10-9 M) [30]
JAK inhibitor 17b Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.8 pIC50 22
⤷ pIC50 8.8 (IC50 1.67x10-9 M) [22]
PF-956980 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.6 pIC50 28
⤷ pIC50 8.6 (IC50 2.8x10-9 M) [28]
LASW1393 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 5
⤷ pIC50 8.5 (IC50 3.5x10-9 M) [5]
JAK inhibitor I Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 52
⤷ pIC50 8.3 (IC50 5x10-9 M) [52]
compound 2 [PMID: 15546730] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.2 pIC50 16
⤷ pIC50 8.2 (IC50 6x10-9 M) [16]
cerdulatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 18
⤷ pIC50 8.1 (IC50 8x10-9 M) [18]
decernotinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.1 – 8.9 pIC50 17
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [17]
pIC50 7.1 (IC50 7.44x10-8 M) [17]
lepzacitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition >8.0 pIC50 3
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [3]
JAK3 inhibitor 32 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 11
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [11]
delgocitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.9 pIC50 41
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [41]
tofacitinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.7 – 9.0 pIC50 14,17,24,42
⤷ pIC50 8.2 (IC50 6x10-9 M) [42]
pIC50 6.7 – 9.0 (IC50 2.1x10-7 – 1x10-9 M) [14,24]
pIC50 7.3 (IC50 5.5x10-8 M) [17]
Description: In a biochemical enzyme assay.
compound 1d [PMID: 21493067] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 55
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [55]
lazertinib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition >7.7 pIC50 49
⤷ pIC50 >7.7 (IC50 <2x10-8 M) [49]
Description: In a biochemical enzyme activity assay.
PRN694 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 63
⤷ pIC50 7.5 (IC50 3x10-8 M) [63]
momelotinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 – 8.2 pIC50 4,43
⤷ pIC50 8.2 (IC50 6.1x10-9 M) [4]
pIC50 6.8 (IC50 1.55x10-7 M) [43]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 10
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [10]
ilginatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 40
⤷ pIC50 7.4 (IC50 3.9x10-8 M) [40]
compound 18e [PMID: 31670517] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 61
⤷ pIC50 7.4 (IC50 3.9x10-8 M) [61]
ruxolitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.3 – 8.5 pIC50 17,29
⤷ pIC50 8.5 (IC50 3.22x10-9 M) [29]
pIC50 6.3 (IC50 4.87x10-7 M) [17]
compound 8l [PMID: 36053746] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 36
⤷ pIC50 7.3 (IC50 4.62x10-8 M) [36]
gandotinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 38
⤷ pIC50 7.3 (IC50 4.8x10-8 M) [38]
JAK3 inhibitor 34 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 11
⤷ pIC50 7.3 (IC50 4.9x10-8 M) [11]
poseltinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition >7.3 pIC50 12
⤷ pIC50 >7.3 (IC50 <5x10-8 M) [12]
Description: Biochemical assay result. Binned IC50 value provided in patent.
CEE321 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 51
⤷ pIC50 7.2 (IC50 5.9x10-8 M) [51]
PF-06263276 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 33
⤷ pIC50 7.2 (IC50 5.99x10-8 M) [33]
BMS-911543 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.1 pIC50 45
⤷ pIC50 7.1 (IC50 7.3x10-8 M) [45]
JAK3 inhibitor IV Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.1 pIC50 9
⤷ pIC50 7.1 (IC50 7.9x10-8 M) [9]
lorpucitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pIC50 34
⤷ pIC50 7.0 (IC50 9.22x10-8 M) [34]
Description: Determined in a biochemical high-throughput mass spectrometry (HTMS) assay.
compound 25ap [PMID: 37796543] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pIC50 62
⤷ pIC50 7.0 (IC50 9.1x10-8 M) [62]
compound 13ac [PMID: 33256400] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pIC50 60
⤷ pIC50 7.0 (IC50 9.4x10-8 M) [60]
oclacitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pIC50 7
⤷ pIC50 7.0 (IC50 9.51x10-8 M) [7]
mivavotinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 35
⤷ pIC50 6.9 (IC50 1.15x10-7 M) [35]
JAK inhibitor 20a Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 22
⤷ pIC50 6.9 (IC50 1.144x10-7 M) [22]
CEP-33779 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.8 pIC50 21
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [21]
XL019 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 25
⤷ pIC50 6.7 (IC50 2.142x10-7 M) [25]
compound 19a [PMID: 24359159] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 48
⤷ pIC50 6.7 (IC50 2.2x10-7 M) [48]
filgotinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 53
⤷ pIC50 6.5 (IC50 8.1x10-7 M) [53]
solcitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.4 pIC50 8
⤷ pIC50 6.4 (IC50 4.08x10-7 M) [8]
pacritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 pIC50 56
⤷ pIC50 6.3 (IC50 5.2x10-7 M) [56]
baricitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.1 pIC50 17
⤷ pIC50 6.1 (IC50 7.87x10-7 M) [17]
NIK inhibitor 12f Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.1 pIC50 64
⤷ pIC50 6.1 (IC50 8.92x10-7 M) [64]
Description: Inhibitory concentration determined in a Reaction Biology kinase sreening assay.
compound 30 [PMID: 37057760] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.0 pIC50 46
⤷ pIC50 6.0 (IC50 9.54x10-7 M) [46]
fedratinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.0 pIC50 39
⤷ pIC50 6.0 (IC50 1x10-6 M) [39]
acalabrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition <6.0 pIC50 10
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [10]
SAR-20347 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.8 pIC50 58
⤷ pIC50 5.8 (IC50 1.437x10-6 M) [58]
Description: In a TR-FRET assay.
JAK3 inhibitor II Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.7 pIC50 15
⤷ pIC50 5.7 (IC50 1.8x10-6 M) [15]
upadacitinib Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.6 pIC50 54
⤷ pIC50 5.6 (IC50 2.3x10-6 M) [54]
AZD1480 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.4 pIC50 27
⤷ pIC50 5.4 (IC50 3.63x10-6 M) [27]
brepocitinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 5.2 pIC50 23
⤷ pIC50 5.2 (IC50 6.494x10-6 M) [23]
peficitinib Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition >- pIC50 32
⤷ pIC50 [32]
Inhibitor Comments
The IC50 for filgotinib vs. JAK3 is >10 μM [17].
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SJ988497 Small molecule or natural product Click here for species-specific activity table Hs Binding 8.9 pKd 13
⤷ pKd 8.9 (Kd 1.4x10-9 M) [13]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 19,57
Key to terms and symbols Click column headers to sort
Target used in screen: JAK3(JH1domain-catalytic)
Ligand Sp. Type Action Value Parameter
tofacitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.8 pKd
ruxolitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.7 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.6 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.9 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.4 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 2,26
Key to terms and symbols Click column headers to sort
Target used in screen: JAK3/JAK3
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
EGFR/ErbB-2/ErbB-4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition -0.2 51.0 59.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.4 1.0 1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 0.5 0.0 0.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.7 0.0 0.5
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 0.8 1.0 1.0
tofacitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 1.9
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 1.9 8.0 9.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.4 1.0 2.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 4.8 6.0 1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.2 0.0 2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Psoriatic skin samples show elevated JAK3 (and JAK1) expression, with signalling predominantly through STAT3 [1]. JAK3 upregulation is observed in skin cells and dermal inflammatory infiltrate.
Noncoding mutation which creates a dominant splice site and reduces wild-type JAK3 protein expression is the cause of SCID/CID in siblings [44].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Combined immunodeficiency
Description: Combined immunodeficiency evolving into predominant CD4+ lymphopenia
Role:  Missense mutation in the kinase domain of JAK3 leads to JAK3 deficiency and manifests as combined immunodeficiency evolving into predominant CD4+ lymphopenia.
Disease:  Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative
Synonyms: T-B+ severe combined immunodeficiency due to JAK3 deficiency [Orphanet: ORPHA35078]
Disease Ontology: DOID:0060008
OMIM: 600802
Orphanet: ORPHA35078
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Human
Description:  This mutation causes combined immunodeficiency evolving into predominant CD4+ lymphopenia.
Amino acid change:  Cys1066Arg
Nucleotide change:  T3196C
References:  6
Type:  Naturally occurring SNP
Species:  Human
Description:  An inherited non-coding homozygous mutation creating a dominant splice site and reduced wild-type protein expression causes SCID/CID.
Nucleotide change:  c.2652C>T
References:  44

References

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1. Alves de Medeiros AK, Speeckaert R, Desmet E, Van Gele M, De Schepper S, Lambert J. (2016) JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases. PLoS ONE, 11 (10): e0164080. [PMID:27711196]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

3. Anderson DR, Hockerman SL, Blinn JR, Jacobsen EJ. (2019) Substituted pyrrolopyrimidine jak inhibitors and methods of making and using the same. Patent number: WO2019090158A1. Assignee: Aclaris Therapeutics, Inc.. Priority date: 02/10/2029. Publication date: 02/08/2029.

4. Asshoff M, Petzer V, Warr MR, Haschka D, Tymoszuk P, Demetz E, Seifert M, Posch W, Nairz M, Maciejewski P et al.. (2017) Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood, 129 (13): 1823-1830. [PMID:28188131]

5. Bach J, Eastwood P, González J, Gómez E, Alonso JA, Fonquerna S, Lozoya E, Orellana A, Maldonado M, Calaf E et al.. (2019) Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases. J Med Chem, 62 (20): 9045-9060. [PMID:31609613]

6. Ban SA, Salzer E, Eibl MM, Linder A, Geier CB, Santos-Valente E, Garncarz W, Lion T, Ott R, Seelbach C et al.. (2014) Combined immunodeficiency evolving into predominant CD4+ lymphopenia caused by somatic chimerism in JAK3. J Clin Immunol, 34 (8): 941-53. [PMID:25205547]

7. Berlinski PJ, Birchmeier MJ, Bowman JW, Gonzales AJ, Kamerling SG, Mann DW, Mitton-Fry MJ. (2010) Pyrrolo[2,3-d]pyrimidine compounds. Patent number: WO2010020905. Assignee: Pfizer Inc.. Priority date: 20/08/2008. Publication date: 25/02/2010.

8. Blanc J. (2010) Novel compound useful for the treatment of degenerative and inflammatory diseases. Patent number: WO2010149771. Assignee: Galapagos Nv, Menet, Christel Jeanne Marie. Priority date: 26/06/2009. Publication date: 29/12/2010.

9. Brown GR, Bamford AM, Bowyer J, James DS, Rankine N, Tang E, Torr V, Culbert EJ. (2000) Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett, 10 (6): 575-9. [PMID:10741557]

10. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR et al.. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med, 374 (4): 323-32. [PMID:26641137]

11. Casimiro-Garcia A, Trujillo JI, Vajdos F, Juba B, Banker ME, Aulabaugh A, Balbo P, Bauman J, Chrencik J, Coe JW et al.. (2018) Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors. J Med Chem, 61 (23): 10665-10699. [PMID:30423248]

12. Cha MY, Kang SJ, Kim MR, Lee JY, Jeon JY, Jo MG, Kwak EJ, Lee KO, Ha TH, Suh KH, Kim MS. (2011) Novel fused pyrimidine derivatives for inhd3ition of tyrosine kinase activity. Patent number: WO2011162515A2. Assignee: Hanmi Holdings Co. , Ltd.. Priority date: 23/06/2010. Publication date: 29/12/2011.

13. Chang Y, Min J, Jarusiewicz JA, Actis M, Yu-Chen Bradford S, Mayasundari A, Yang L, Chepyala D, Alcock LJ, Roberts KG et al.. (2021) Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia. Blood, 138 (23): 2313-2326. [PMID:34110416]

14. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH et al.. (2003) Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science, 302 (5646): 875-8. [PMID:14593182]

15. Changelian PS, Moshinsky D, Kuhn CF, Flanagan ME, Munchhof MJ, Harris TM, Whipple DA, Doty JL, Sun J, Kent CR et al.. (2008) The specificity of JAK3 kinase inhibitors. Blood, 111 (4): 2155-7. [PMID:18094329]

16. Chen P, Norris D, Das J, Spergel SH, Wityak J, Leith L, Zhao R, Chen BC, Pitt S, Pang S et al.. (2004) Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg Med Chem Lett, 14 (24): 6061-6. [PMID:15546730]

17. Clark JD, Flanagan ME, Telliez JB. (2014) Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem, 57 (12): 5023-38. [PMID:24417533]

18. Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. (2014) The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther, 351 (3): 538-48. [PMID:25253883]

19. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

20. Dengler HS, Wu X, Peng I, Rinderknecht CH, Kwon Y, Suto E, Kohli PB, Liimatta M, Barrett K, Lloyd J et al.. (2018) Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma. Sci Transl Med, 10 (468): eaao2151. [PMID:30463918]

21. Dugan BJ, Gingrich DE, Mesaros EF, Milkiewicz KL, Curry MA, Zulli AL, Dobrzanski P, Serdikoff C, Jan M, Angeles TS et al.. (2012) A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J Med Chem, 55 (11): 5243-54. [PMID:22594690]

22. Elsayed MSA, Nielsen JJ, Park S, Park J, Liu Q, Kim CH, Pommier Y, Agama K, Low PS, Cushman M. (2018) Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors in the Benzo[ c]pyrrolo[2,3- h][1,6]naphthyridin-5-one (BPN) Series. J Med Chem, 61 (23): 10440-10462. [PMID:30460842]

23. Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, Clark JD, Dowty ME, Efremov IV, Flick A et al.. (2018) Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841). J Med Chem, 61 (19): 8597-8612. [PMID:30113844]

24. Flanagan ME, Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C, Doty JL, Elliott EA, Fisher MB, Hines M et al.. (2010) Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem, 53 (24): 8468-84. [PMID:21105711]

25. 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]

26. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

27. Gozgit JM, Bebernitz G, Patil P, Ye M, Parmentier J, Wu J, Su N, Wang T, Ioannidis S, Davies A et al.. (2008) Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2. J Biol Chem, 283 (47): 32334-43. [PMID:18775810]

28. Hanan EJ, Liang J, Wang X, Blake RA, Blaquiere N, Staben ST. (2020) Monomeric Targeted Protein Degraders. J Med Chem, 63 (20): 11330-11361. [PMID:32352776]

29. 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]

30. 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]

31. Hudson R, Kozak J, Fatheree PR, Podesto DD, Brandt GEL, Fleury M, Beausoleil A-M, Huang X, Thalladi VR. (2016) Naphthyridine compounds as jak kinase inhibitors. Patent number: WO2016191524A1. Assignee: Theravance Biopharma R&D. Priority date: 28/05/2015. Publication date: 01/12/2016.

32. Ito M, Yamazaki S, Yamagami K, Kuno M, Morita Y, Okuma K, Nakamura K, Chida N, Inami M, Inoue T et al.. (2017) A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model. J Pharmacol Sci, 133 (1): 25-33. [PMID:28117214]

33. Jones P, Storer RI, Sabnis YA, Wakenhut FM, Whitlock GA, England KS, Mukaiyama T, Dehnhardt CM, Coe JW, Kortum SW et al.. (2017) Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin. J Med Chem, 60 (2): 767-786. [PMID:27983835]

34. Koudriakova T, Kreutter K, Leonard K, Rizzolio M, Smith RC, Tichenor MS, Wang A. (2018) Small molecule inhibitors of the JAK family of kinases. Patent number: WO2018112379A1. Assignee: Janssen Pharmaceutica. Priority date: 16/12/2016. Publication date: 21/06/2018.

35. Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A et al.. (2016) Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg Med Chem Lett, 26 (24): 5947-5950. [PMID:27839918]

36. Liang X, Xie Y, Liu X, Xu H, Ren H, Tang S, Liu Q, Huang M, Shao X, Li C et al.. (2022) Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis. J Med Chem, 65 (18): 11949-11969. [PMID:36053746]

37. Long DD, Smith C, Thompson C. (2020) DIMETHYL AMINO AZETIDINE AMIDES AS JAK INHIBITORS. Patent number: WO/2020/051105. Assignee: THERAVANCE BIOPHARMA. Priority date: 04/09/2018. Publication date: 12/03/2020.

38. 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]

39. 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]

40. 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]

41. Noji S, Hara Y, Miura T, Yamanaka H, Maeda K, Hori A, Yamamoto H, Obika S, Inoue M, Hase Y et al.. (2020) Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin Disorders. J Med Chem, 63 (13): 7163-7185. [PMID:32511913]

42. Ostrovskyi D, Rumpf T, Eib J, Lumbroso A, Slynko I, Klaeger S, Heinzlmeir S, Forster M, Gehringer M, Pfaffenrot E et al.. (2016) Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1). Future Med Chem, 8 (13): 1537-51. [PMID:27572962]

43. Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. (2009) CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia, 23 (8): 1441-5. [PMID:19295546]

44. Platt CD, Massaad MJ, Cangemi B, Schmidt B, Aldhekri H, Geha RS. (2017) Janus kinase 3 deficiency caused by a homozygous synonymous exonic mutation that creates a dominant splice site. J Allergy Clin Immunol, 140 (1): 268-271.e6. [PMID:27956217]

45. 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]

46. Qiu Q, Chi F, Zhou D, Xie Z, Liu Y, Wu H, Yin Z, Shi W, Qian H. (2023) Exploration of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Bispecific Inhibitors Based on the Moiety of Fedratinib for Treatment of Both Hematologic Malignancies and Solid Cancers. J Med Chem, 66 (8): 5753-5773. [PMID:37057760]

47. Soth M, Hermann JC, Yee C, Alam M, Barnett JW, Berry P, Browner MF, Frank K, Frauchiger S, Harris S et al.. (2013) 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. J Med Chem, 56 (1): 345-56. [PMID:23214979]

48. Su Q, Ioannidis S, Chuaqui C, Almeida L, Alimzhanov M, Bebernitz G, Bell K, Block M, Howard T, Huang S et al.. (2014) Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors. J Med Chem, 57 (1): 144-58. [PMID:24359159]

49. Suh B-C, Salgaonkar PD, Lee J, Koh JS, Song H-J, Lee IY, Lee J, Jung DS, Kim J-H, Kim S-W. (2016) Compounds and compositions for modulating EGFR mutant kinase activities. Patent number: WO2016060443A2. Assignee: Yuhan Corporation. Priority date: 13/10/2014. Publication date: 21/04/2016.

50. Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, Noji S, Shiozaki M, Matsuo A, Shinozaki Y et al.. (2015) Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res, 64 (1): 41-51. [PMID:25387665]

51. Thoma G, Duthaler RO, Waelchli R, Hauchard A, Bruno S, Strittmatter-Keller U, Orjuela Leon A, Viebrock S, Aichholz R, Beltz K et al.. (2023) Discovery and Characterization of the Topical Soft JAK Inhibitor CEE321 for Atopic Dermatitis. J Med Chem, 66 (3): 2161-2168. [PMID:36657024]

52. Thompson JE, Cubbon RM, Cummings RT, Wicker LS, Frankshun R, Cunningham BR, Cameron PM, Meinke PT, Liverton N, Weng Y et al.. (2002) Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett, 12 (8): 1219-23. [PMID:11934592]

53. 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]

54. Voss JW, Camp HS, Padley RJ. (2015) Jak1 selective inhibitor and uses thereof. Patent number: WO2015061665. Assignee: Abbvie Inc.. Priority date: 24/10/2013. Publication date: 30/04/2015.

55. 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]

56. William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET et al.. (2011) Discovery of the macrocycle 11-(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 Med Chem, 54 (13): 4638-58. [PMID:21604762]

57. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

58. Works MG, Yin F, Yin CC, Yiu Y, Shew K, Tran TT, Dunlap N, Lam J, Mitchell T, Reader J et al.. (2014) Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis. J Immunol, 193 (7): 3278-87. [PMID:25156366]

59. Xu X, Mao L, Xu W, Tang W, Zhang X, Xi B, Xu R, Fang X, Liu J, Fang C et al.. (2016) AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients. Mol Cancer Ther, 15 (11): 2586-2597. [PMID:27573423]

60. Yang T, Hu M, Chen Y, Xiang M, Tang M, Qi W, Shi M, He J, Yuan X, Zhang C et al.. (2020) N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms. J Med Chem, 63 (23): 14921-14936. [PMID:33256400]

61. Yang T, Hu M, Qi W, Yang Z, Tang M, He J, Chen Y, Bai P, Yuan X, Zhang C et al.. (2019) Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms. J Med Chem, 62 (22): 10305-10320. [PMID:31670517]

62. Zhao C, Zhang Y, Zhang J, Li S, Liu M, Geng Y, Liu F, Chai Q, Meng H, Li M et al.. (2023) Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer. J Med Chem, 66 (20): 14150-14174. [PMID:37796543]

63. Zhong Y, Dong S, Strattan E, Ren L, Butchar JP, Thornton K, Mishra A, Porcu P, Bradshaw JM, Bisconte A et al.. (2015) Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. J Biol Chem, 290 (10): 5960-78. [PMID:25593320]

64. Zhu Y, Ma Y, Zu W, Song J, Wang H, Zhong Y, Li H, Zhang Y, Gao Q, Kong B et al.. (2020) Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis. J Med Chem, 63 (13): 6748-6773. [PMID:32479083]

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Janus kinase (JakA) family: Janus kinase 3. Last modified on 06/10/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2049.