JAK1

Summary

JAK1 (Janus kinase 1, HGNC:6190) is a protein-coding gene on chromosome 1p31.3, encoding Tyrosine-protein kinase JAK1 (P23458). Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. In precision oncology, JAK1 OVEREXPRESSION confers sensitivity to Ruxolitinib in Sarcoma (CIViC Level C); 3 further curated variant–drug associations are listed below.

This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 3716 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammation, immune dysregulation, and eosinophilia (Definitive, ClinGen)
• GWAS associations: 23
• Clinical variants (ClinVar): 862 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes — 68 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 8 cancer types
• MANE Select transcript: NM_002227

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6190
Approved symbol	JAK1
Name	Janus kinase 1
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	JAK1A, JTK3
Ensembl gene	ENSG00000162434
Ensembl biotype	protein_coding
OMIM	147795
Entrez	3716

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 33 protein_coding, 5 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000342505, ENST00000465376, ENST00000471473, ENST00000481702, ENST00000494904, ENST00000671746, ENST00000671929, ENST00000671954, ENST00000672099, ENST00000672179, ENST00000672247, ENST00000672434, ENST00000672574, ENST00000672751, ENST00000672903, ENST00000673046, ENST00000673220, ENST00000673246, ENST00000673254, ENST00000673314, ENST00000673502, ENST00000699259, ENST00000699260, ENST00000699261, ENST00000699262, ENST00000699263, ENST00000699310, ENST00000699311, ENST00000699312, ENST00000699313, ENST00000699314, ENST00000893439, ENST00000893440, ENST00000893441, ENST00000893442, ENST00000893443, ENST00000893444, ENST00000893445, ENST00000930718, ENST00000930721, ENST00000970943, ENST00000970944, ENST00000970945, ENST00000970946, ENST00000970947

RefSeq mRNA: 8 — MANE Select: NM_002227 NM_001320923, NM_001321852, NM_001321853, NM_001321854, NM_001321855, NM_001321856, NM_001321857, NM_002227

CCDS: CCDS41346, CCDS90968

Canonical transcript exons

ENST00000342505 — 25 exons

Exon	Start	End
ENSE00001065127	64841245	64841339
ENSE00001065130	64837932	64838104
ENSE00001065133	64883277	64883475
ENSE00001065136	64838465	64838589
ENSE00001065139	64839603	64839795
ENSE00001065145	64873370	64873523
ENSE00001065148	64835396	64835506
ENSE00001065152	64857656	64857779
ENSE00001065154	64841451	64841601
ENSE00001065160	64864787	64864972
ENSE00001065162	64836098	64836215
ENSE00001065165	64879025	64879148
ENSE00001065168	64860105	64860262
ENSE00001065174	64850804	64850910
ENSE00001065178	64866866	64867208
ENSE00001065179	64869311	64869474
ENSE00001065183	64855509	64855698
ENSE00001370496	64833229	64834657
ENSE00001454262	64886259	64886341
ENSE00001454263	64966333	64966549
ENSE00003507779	64846649	64846736
ENSE00003537127	64844754	64844889
ENSE00003570695	64844064	64844215
ENSE00003598953	64847532	64847675
ENSE00003621841	64845513	64845640

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.3561 / max 918.0962, expressed in 1819 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12673	49.7107	1816
12686	1.9469	614
12672	1.2503	772
12685	0.6304	288
12665	0.3602	146
12664	0.3068	129
12687	0.1509	53

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	98.66	gold quality
skin of hip	UBERON:0001554	98.37	gold quality
calcaneal tendon	UBERON:0003701	98.37	gold quality
epithelium of nasopharynx	UBERON:0001951	98.28	gold quality
lymph node	UBERON:0000029	98.18	gold quality
cartilage tissue	UBERON:0002418	98.12	gold quality
superficial temporal artery	UBERON:0001614	98.11	gold quality
upper leg skin	UBERON:0004262	98.01	gold quality
parietal pleura	UBERON:0002400	97.88	gold quality
gluteal muscle	UBERON:0002000	97.87	gold quality
sperm	CL:0000019	97.84	gold quality
palpebral conjunctiva	UBERON:0001812	97.82	gold quality
pleura	UBERON:0000977	97.78	gold quality
right lung	UBERON:0002167	97.78	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.74	gold quality
lower lobe of lung	UBERON:0008949	97.70	gold quality
blood	UBERON:0000178	97.67	gold quality
visceral pleura	UBERON:0002401	97.67	gold quality
granulocyte	CL:0000094	97.64	gold quality
adipose tissue	UBERON:0001013	97.63	gold quality
connective tissue	UBERON:0002384	97.61	gold quality
trabecular bone tissue	UBERON:0002483	97.58	gold quality
vermiform appendix	UBERON:0001154	97.57	gold quality
male germ cell	CL:0000015	97.37	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.36	gold quality
spleen	UBERON:0002106	97.32	gold quality
upper lobe of lung	UBERON:0008948	97.32	gold quality
caecum	UBERON:0001153	97.30	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.30	gold quality
upper lobe of left lung	UBERON:0008952	97.27	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	79.19
E-CURD-122	yes	45.97
E-MTAB-6701	yes	31.62
E-HCAD-10	yes	28.19
E-CURD-88	yes	16.99
E-MTAB-9388	yes	12.26
E-CURD-46	yes	12.19
E-MTAB-10042	yes	11.65
E-MTAB-6678	yes	11.02
E-MTAB-9067	yes	3.67
E-GEOD-150728	no	1706.97
E-MTAB-9467	no	31.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
IL6ST	Activation
STAT3	Activation

Upstream regulators (CollecTRI, top): BRCA1, FOXO3, IRF8, NFKB, RELA, SPI1, STAT1, STAT6, YBX1

miRNA regulators (miRDB)

82 targeting JAK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-466	99.67	70.85	2863

Literature-anchored findings (GeneRIF, showing 40)

• role in regulating oncostatin M receptor surface expression (PMID:11786531)
• requirement in interferon-gamma-mediated inhibition in human chondrocytes (PMID:12223098)
• interaction with cytokine receptors and role in activation of cytokine and growth factor signaling pathways (PMID:12374810)
• Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation (PMID:12620806)
• Data suggest there is no defect in the JAK/STAT pathway in the tested melanoma cell lines, and that interferon resistance must be mediated through other components. (PMID:12777975)
• In the IFN signaling pathway leading to STAT activation, both JAK1 and TYK2 are essential, whereas NF-kappaB activation requires only TYK2. (PMID:15883164)
• the SH2 domain is structurally important for cytokine receptor binding and surface expression of the oncostatin m receptor (PMID:15894543)
• Data show that medroxyprogesterone acetate treatment of mammary tumor cells up-regulated Stat3 protein expression and induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation. (PMID:15923602)
• JAK1 and JAK2 must work cooperatively and not independently and that their actions are dependent on having normal kinase activity to trigger downstream signals leading to Interleukin-3 independent proliferation (PMID:15988755)
• Two different heterozygous mutations in the Janus kinase 1 (JAK1) gene result in complete loss of the protein in several different prostate cancer cell lines. (PMID:16102578)
• mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases (PMID:16239216)
• JAK1/2 are client proteins of Hsp90 alpha and beta; Hsp90 and CDC37 play a critical role in types I and II interferon pathways (PMID:16280321)
• These results suggest that the JAK1-JH7-3 domains are required for interleukin-3 receptor common beta subunit interaction and abolish wild type JAK1 and JAK2-mediated signaling. (PMID:16767694)
• IFN-alpha-induced apoptosis in the MM cell lines U266 and H929 was completely blocked by a specific inhibitor of Jak1 (PMID:17158029)
• Functional cross-talk between Ras/extracellular signal-regulated kinase (Erk) and IL-4/Janus kinase 1 (JAK1)/STAT6 contributes to the regulation of IL-4 transcription in T cells. (PMID:17433443)
• The results indicate that Adenovirus down-regulates host epithelial cell Jak1 to assure inhibition of the antiviral effects of multiple mediators to subvert airway defense responses and establish a productive infection. (PMID:17641294)
• Mealse virus V protein can block the direct phosphorylation of STAT1 by Jak1 to escape IFN alpha/beta signaling. (PMID:17686504)
• Small interference RNAs specific for Jak1, was identified that reproducibly reduce viral RNA and viral protein levels in hepatitis C virus replicon-bearing cells (PMID:17951261)
• two independent and indispensable signaling pathways-1) JAK1-associated PI3K signaling and 2) Act1/TRAF6/TAK1-mediated NF-kappaB activation-are stimulated by IL-17A to regulate gene induction in human airway epithelial cells. (PMID:17982039)
• identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients (PMID:18160671)
• The structural integrity of both the FERM domain and of the kinase domain of JAK1 is essential for both receptor binding and catalytic function/autoinhibition (PMID:18178840)
• Theses findings illustrate the biologic significance of JAK1, 2/STAT3 signaling in colorectal cancer (CRC) progression and provide novel evidence that the JAK/STAT3 pathway may be a new potential target for therapy of CRC. (PMID:18320073)
• These findings implicate dysregulated JAK1 function in acute lymphoblastic leukemia. (PMID:18362173)
• JAK-STAT3 signaling pathway participates in regulating the invasion and metastasis of human breast cancer. (PMID:18390202)
• The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) inhibits activation of the JAK1–>STAT3 pathway by forming adducts with both JAK1 and STAT3. (PMID:18413761)
• murine OSMR initiates STAT5 activation directly via the receptor bound Janus kinases. Intriguingly, the murine receptor preferentially recruits JAK2, whereas the human receptor seems to have a higher affinity for JAK1. (PMID:18430728)
• Some of the JAK1 and JAK3 mutations may to be functional and contributes to cancer development, especially to T-ALL development. (PMID:18559588)
• JAK/STAT-1 signaling pathway was necessary and sufficient to mediate the down-regulation of FcRn gene expression by IFN-gamma (PMID:18566411)
• JAK/STAT3 and ERK1/2 signaling activation is involved in leptin-mediated proliferation of renal cell carcinoma Caki-2 cells (PMID:18787400)
• Iron chelators and hypoxia mimetics inhibit IFNgamma-mediated Jak-STAT signaling (PMID:18787531)
• IFN-gamma down-regulates ABCA1 expression by inhibiting LXRalpha in a JAK/STAT signaling pathway-dependent manner (PMID:18789440)
• TCPTP is a negative regulator of SFK, JAK1 and STAT3 signalling during the cell cycle. (PMID:18948751)
• Jak-1 was expressed at higher levels in patients with diabetic nephropathy than in control subjects. (PMID:19017763)
• IL-9Ralpha and IL-2Rbeta homodimers efficiently mediate constitutive activation of ALL-associated JAK1 mutants. (PMID:19139102)
• Western blot analysis of JAK1 in 293T cells showed that the E966V and Del(966-989) variants displayed weak JAK1 auto-phosphorylation, comparable to wild type JAK1, and in contrast to the strongly phosphorylated R724H mutant. (PMID:19176360)
• IL-5 induces cell proliferation and anti-apoptosis through the JAK/c-Myc pathway, and JAK1 and JAK2 activation participate in IL-5-induced up-regulation of c-Myc. (PMID:19180571)
• JAK1 mutation may contribute to the tumor development in liver cancer. (PMID:19239328)
• Data show that the mechanism of G-CSF-induced chemotaxis appears to involve the phosphorylation of JAK1/STAT3 pathway. (PMID:19255588)
• Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. (PMID:19457567)
• Genomic resequencing of JAK1, JAK2, JAK3, and TYK2 in 187 diagnostic samples from a high risk B-progenitor ALL cohort that had available DNA and gene expression profiling data identified mutations in JAK1, JAK2, and JAK3 in 20 patients (10.7%). (PMID:19470474)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	jak1	ENSDARG00000020625
mus_musculus	Jak1	ENSMUSG00000028530
rattus_norvegicus	Jak1	ENSRNOG00000011157

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), ZAP70 (ENSG00000115085), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), YES1 (ENSG00000176105), FES (ENSG00000182511), LCK (ENSG00000182866), SRC (ENSG00000197122), LYN (ENSG00000254087)

Protein

Protein identifiers

Tyrosine-protein kinase JAK1 — P23458 (reviewed: P23458)

Alternative names: Janus kinase 1

All UniProt accessions (15): A0A0A0N0M2, A0A5F9ZH07, A0A5F9ZH73, A0A5F9ZHI1, A0A5F9ZHK2, A0A5F9ZHN8, A0A5F9ZHW0, A0A5F9ZI01, P23458, A0A5F9ZI39, A0A8V8TMY8, A0A8V8TN11, A0A8V8TN56, A0A8V8TPG3, A0A8V8TPQ9

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor as well as interleukin (IL)-10 receptor. Kinase partner for the type I interferon receptor IFNAR2. In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins. Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors.

Subunit / interactions. Interacts with IL31RA. Interacts with IFNGR1. Interacts with JAKMIP1. Interacts with SHB. Interacts (via N-terminus) with IL2RB and IL10RA (via its cytoplasmic domain). Interacts with FER.

Subcellular location. Endomembrane system.

Tissue specificity. Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue.

Post-translational modifications. Autophosphorylated. Phosphorylated by TYK2 on tyrosine residues in response to type-I interferon signaling, leading to its activation. Phosphorylated on tyrosine residues in response to interferon gamma signaling. Dephosphorylation of Tyr-1034 and Tyr-1035 by PTPN2 negatively regulates cytokine-mediated signaling. Ubiquitinated by RNF125; leading to its degradation by the proteasome.

Disease relevance. Autoinflammation, immune dysregulation, and eosinophilia (AIIDE) [MIM:618999] An autosomal dominant disorder characterized by immune dysregulation, severe atopic dermatitis, and chronic gastrointestinal inflammation. Additional features include asthma, food or environmental allergies, as well as poor overall growth with short stature. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Mn(2+) was used in the in vitro kinase assay but Mg(2+) is likely to be the in vivo cofactor.

Domain organisation. The protein kinase 1 domain is also called the pseudokinase domain and has a regulatory role through the transactivation of other JAK kinases associated with signaling receptors. The protein kinase 2 domain is the catalytically active domain. The FERM domain mediates interaction with JAKMIP1.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.

RefSeq proteins (8): NP_001307852, NP_001308781, NP_001308782, NP_001308783, NP_001308784, NP_001308785, NP_001308786, NP_002218* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016251	Tyr_kinase_non-rcpt_Jak/Tyk2	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR020635	Tyr_kinase_cat_dom	Domain
IPR020776	Tyr_kinase_non-rcpt_Jak1	Family
IPR035963	FERM_2	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR041046	FERM_F2	Domain
IPR041155	FERM_F1	Domain
IPR041381	JAK1-3/TYK2_PHL_dom	Domain
IPR051286	JAK	Family

Pfam: PF07714, PF17887, PF18377, PF18379, PF21990

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (129 total): strand 49, helix 46, turn 13, modified residue 5, domain 4, sequence variant 3, sequence conflict 3, mutagenesis site 2, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

51 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6N7A	X-RAY DIFFRACTION	1.33
6N77	X-RAY DIFFRACTION	1.64
6N7C	X-RAY DIFFRACTION	1.69
6GGH	X-RAY DIFFRACTION	1.7
6RSH	X-RAY DIFFRACTION	1.71
8S85	X-RAY DIFFRACTION	1.75
6RSD	X-RAY DIFFRACTION	1.76
6N7D	X-RAY DIFFRACTION	1.78
4GS0	X-RAY DIFFRACTION	1.8
4L00	X-RAY DIFFRACTION	1.8
6ELR	X-RAY DIFFRACTION	1.8
6RSB	X-RAY DIFFRACTION	1.8
6RSE	X-RAY DIFFRACTION	1.8
6N7B	X-RAY DIFFRACTION	1.81
6AAH	X-RAY DIFFRACTION	1.83
6N78	X-RAY DIFFRACTION	1.83
5WO4	X-RAY DIFFRACTION	1.84
6RSC	X-RAY DIFFRACTION	1.85
6SM8	X-RAY DIFFRACTION	1.85
4E5W	X-RAY DIFFRACTION	1.86
3EYG	X-RAY DIFFRACTION	1.9
4E4N	X-RAY DIFFRACTION	1.9
4IVB	X-RAY DIFFRACTION	1.9
4L01	X-RAY DIFFRACTION	1.9
4IVD	X-RAY DIFFRACTION	1.93
3EYH	X-RAY DIFFRACTION	2
4E4L	X-RAY DIFFRACTION	2
6SMB	X-RAY DIFFRACTION	2.04
6BBU	X-RAY DIFFRACTION	2.08
4I5C	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23458-F1	85.68	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1003 (proton acceptor)

Ligand- & substrate-binding residues (2): 881–889; 908

Post-translational modifications (5): 228, 1034, 1035, 1, 3

Mutagenesis-validated functional residues (2):

Position	Phenotype
658	constitutively active. increased receptor signaling pathway via jak-stat.
908	loss of protein tyrosine kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

52 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-112411	MAPK1 (ERK2) activation
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-1266695	Interleukin-7 signaling
R-HSA-449836	Other interleukin signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-6788467	IL-6-type cytokine receptor ligand interactions
R-HSA-877300	Interferon gamma signaling
R-HSA-877312	Regulation of IFNG signaling
R-HSA-8854691	Interleukin-20 family signaling
R-HSA-8983432	Interleukin-15 signaling
R-HSA-8984722	Interleukin-35 Signalling
R-HSA-8985947	Interleukin-9 signaling
R-HSA-9020558	Interleukin-2 signaling
R-HSA-9020591	Interleukin-12 signaling
R-HSA-9020956	Interleukin-27 signaling
R-HSA-9020958	Interleukin-21 signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-912526	Interleukin receptor SHC signaling
R-HSA-912694	Regulation of IFNA/IFNB signaling
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-9732724	IFNG signaling activates MAPKs
R-HSA-9833109	Evasion by RSV of host interferon responses
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane

MSigDB gene sets: 0 (showing top):

GO Biological Process (29): protein phosphorylation (GO:0006468), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), cytokine-mediated signaling pathway (GO:0019221), cell differentiation (GO:0030154), positive regulation of homotypic cell-cell adhesion (GO:0034112), intracellular signal transduction (GO:0035556), interleukin-15-mediated signaling pathway (GO:0035723), interleukin-4-mediated signaling pathway (GO:0035771), interleukin-2-mediated signaling pathway (GO:0038110), interleukin-7-mediated signaling pathway (GO:0038111), interleukin-9-mediated signaling pathway (GO:0038113), interleukin-11-mediated signaling pathway (GO:0038154), type III interferon-mediated signaling pathway (GO:0038196), response to antibiotic (GO:0046677), type II interferon-mediated signaling pathway (GO:0060333), type I interferon-mediated signaling pathway (GO:0060337), growth hormone receptor signaling pathway via JAK-STAT (GO:0060397), interleukin-6-mediated signaling pathway (GO:0070102), T-helper 17 cell lineage commitment (GO:0072540), cellular response to virus (GO:0098586), interleukin-10-mediated signaling pathway (GO:0140105), protein localization to cell-cell junction (GO:0150105), positive regulation of protein localization to nucleus (GO:1900182), positive regulation of sprouting angiogenesis (GO:1903672), regulation of transcription by RNA polymerase II (GO:0006357), regulation of cell-cell adhesion (GO:0022407), regulation of cell adhesion (GO:0030155), regulation of multicellular organismal process (GO:0051239), cellular response to interleukin-7 (GO:0098761)

GO Molecular Function (13): protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), growth hormone receptor binding (GO:0005131), ATP binding (GO:0005524), protein phosphatase binding (GO:0019903), ubiquitin protein ligase binding (GO:0031625), CCR5 chemokine receptor binding (GO:0031730), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (12): nucleus (GO:0005634), cytoplasm (GO:0005737), endosome (GO:0005768), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cytoplasmic side of plasma membrane (GO:0009898), extrinsic component of cytoplasmic side of plasma membrane (GO:0031234), signaling receptor complex (GO:0043235), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by Interleukins	5
Interleukin-2 family signaling	4
Interleukin-12 family signaling	3
Interleukin-6 family signaling	2
RAF-independent MAPK1/3 activation	2
Antimicrobial mechanism of IFN-stimulated genes	1
MAPK1/MAPK3 signaling	1
Interferon Signaling	1
Interferon gamma signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	7
cellular anatomical structure	4
interferon-mediated signaling pathway	3
intracellular anatomical structure	2
plasma membrane	2
phosphorylation	1
protein modification process	1
cell surface receptor signaling pathway via STAT	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cellular developmental process	1
positive regulation of cell-cell adhesion	1
homotypic cell-cell adhesion	1
regulation of homotypic cell-cell adhesion	1
signal transduction	1
cellular response to interleukin-15	1
cellular response to interleukin-4	1
cellular response to interleukin-2	1
cellular response to interleukin-7	1
cellular response to interleukin-9	1
cellular response to type III interferon	1
response to chemical	1
cellular response to type II interferon	1
cellular response to type I interferon	1
growth hormone receptor signaling pathway	1
cellular response to interleukin-6	1
T-helper cell lineage commitment	1
T-helper 17 cell differentiation	1
response to virus	1
protein kinase activity	1
protein tyrosine kinase activity	1
cytokine receptor binding	1
hormone receptor binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
phosphatase binding	1
ubiquitin-like protein ligase binding	1
CCR chemokine receptor binding	1
cation binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

4623 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JAK1	STAT3	P40763	999
JAK1	STAT1	P42224	999
JAK1	IFNAR1	P17181	998
JAK1	IFNAR2	P48551	997
JAK1	IFNGR1	P15260	997
JAK1	IFNGR2	P38484	996
JAK1	SOCS3	O14543	994
JAK1	IL2RG	P31785	994
JAK1	IL4R	P24394	993
JAK1	IL10RA	Q13651	987
JAK1	IL10RB	Q08334	986
JAK1	STAT5B	P51692	986
JAK1	STAT5A	P42229	986
JAK1	TYK2	P29597	984
JAK1	JAK3	P52333	983
JAK1	SOCS1	O15524	983

IntAct

251 interactions, top by confidence:

A	B	Type	Score
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
JAK1	STAT1	psi-mi:“MI:0915”(physical association)	0.760
STAT1	JAK1	psi-mi:“MI:0915”(physical association)	0.760
STAT1	N	psi-mi:“MI:0914”(association)	0.710
JAK1	STAT3	psi-mi:“MI:0915”(physical association)	0.670
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
PDGFRB	PIK3R2	psi-mi:“MI:0914”(association)	0.610
IL6ST	JAK1	psi-mi:“MI:0915”(physical association)	0.560
IL6ST	JAK1	psi-mi:“MI:0914”(association)	0.560
OSMR	JAK1	psi-mi:“MI:0914”(association)	0.560
OSMR	JAK1	psi-mi:“MI:0915”(physical association)	0.560
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
TGFBR2	PIK3R2	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530

BioGRID (355): JAK1 (Affinity Capture-Western), DSP (Affinity Capture-MS), FLG2 (Affinity Capture-MS), JAK1 (Affinity Capture-Western), RNF125 (Affinity Capture-Western), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), JAK1 (Synthetic Lethality), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), JAK1 (Affinity Capture-MS)

ESM2 similar proteins: A5LFV8, A6NC97, B0JZ65, D3ZGS3, O12990, O19064, O23969, O60674, P23458, P42658, P42659, P46101, P52332, P97321, Q01968, Q06137, Q09178, Q13939, Q14BI7, Q16KN5, Q28068, Q2TBM9, Q32N48, Q4J6C6, Q5HZA6, Q5IS50, Q5RAK4, Q5RB23, Q5XI58, Q5ZKL5, Q62120, Q62689, Q6DNF3, Q6J5K9, Q6NVF0, Q6NXK7, Q6P5U7, Q6Q629, Q75R65, Q7JKY3

Diamond homologs: A0A0K3AV08, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, G5EE56, H2KZW3, O01700, O19064, O22558, O43283, O54967, O60674, P00529, P00533, P00534, P00535, P03949, P04412, P06239, P06240, P08069, P08922, P08941, P09760, P09769, P11273, P11362, P13388, P14234, P14616, P14617, P16092, P16591, P18461, P21802, P21803, P21804, P22607

SIGNOR signaling

76 interactions.

A	Effect	B	Mechanism
IL4R	up-regulates	JAK1	binding
PTPN6	down-regulates	JAK1	dephosphorylation
IFNLR1	up-regulates	JAK1	binding
IL20RA	up-regulates	JAK1	binding
IL22RA1	up-regulates	JAK1	binding
PTPN2	“down-regulates activity”	JAK1	dephosphorylation
IFNGR1	up-regulates	JAK1	binding
JAK1	up-regulates	JAK3	phosphorylation
JAK3	up-regulates	JAK1	phosphorylation
IL31RA	up-regulates	JAK1	binding
IL7R	up-regulates	JAK1	binding
JAK1	“up-regulates activity”	STAT3	phosphorylation
AZD1480	down-regulates	JAK1	“chemical inhibition”
N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide	down-regulates	JAK1	“chemical inhibition”
IL6ST	up-regulates	JAK1
SOCS1	down-regulates	JAK1	binding
IL6ST	up-regulates	JAK1	binding
IL2RB	up-regulates	JAK1	binding
ruxolitinib	down-regulates	JAK1	“chemical inhibition”
JAK1	“up-regulates activity”	STAT1	phosphorylation
JAK1	“up-regulates activity”	STAT3	binding
JAK1	“up-regulates activity”	IFNGR1	phosphorylation
JAK1	“up-regulates activity”	IFNGR2	phosphorylation
JAK1	“up-regulates activity”	IFNGR2/INFGR1	phosphorylation
IL4R	“up-regulates activity”	JAK1	phosphorylation
JAK1	“up-regulates activity”	STAT6	phosphorylation
SOCS3	“down-regulates activity”	JAK1	binding
IL10RA	“up-regulates activity”	JAK1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 218 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	19.2×	2e-03
Interleukin-20 family signaling	5	15.7×	2e-03
RAF/MAP kinase cascade	10	4.5×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
cytokine-mediated signaling pathway	14	10.3×	1e-07

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 8 cancer types — ALL, BRCA, MLYM, OVT, PRAD, PROSTATE, STOMACH, UCEC.

Clinical variants and AI predictions

ClinVar

862 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	386
Likely benign	402
Benign	37

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1703484	NM_002227.4(JAK1):c.1786C>G (p.His596Asp)	Pathogenic
977461	NM_002227.4(JAK1):c.2108G>T (p.Ser703Ile)	Pathogenic
998074	NM_002227.4(JAK1):c.2347C>T (p.Leu783Phe)	Likely pathogenic

SpliceAI

4033 predictions. Top by Δscore:

Variant	Effect	Δscore
1:64834653:TAAAC:T	acceptor_gain	1.0000
1:64834655:AAC:A	acceptor_gain	1.0000
1:64834655:AACC:A	acceptor_loss	1.0000
1:64834656:AC:A	acceptor_gain	1.0000
1:64834657:CC:C	acceptor_gain	1.0000
1:64834657:CCTG:C	acceptor_loss	1.0000
1:64834658:C:CC	acceptor_gain	1.0000
1:64835373:A:AC	donor_gain	1.0000
1:64835374:C:CC	donor_gain	1.0000
1:64835400:T:C	donor_gain	1.0000
1:64835504:CAA:C	acceptor_gain	1.0000
1:64835507:C:CC	acceptor_gain	1.0000
1:64835509:A:C	acceptor_gain	1.0000
1:64836096:A:AC	donor_gain	1.0000
1:64836096:ACAG:A	donor_gain	1.0000
1:64836097:C:CC	donor_gain	1.0000
1:64836097:CAG:C	donor_gain	1.0000
1:64836097:CAGC:C	donor_gain	1.0000
1:64837929:TACC:T	donor_loss	1.0000
1:64837931:C:CT	donor_loss	1.0000
1:64837956:T:TA	donor_gain	1.0000
1:64837975:C:CA	donor_gain	1.0000
1:64837980:T:C	donor_gain	1.0000
1:64838100:ATCCC:A	acceptor_gain	1.0000
1:64838101:TCCC:T	acceptor_gain	1.0000
1:64838102:CCC:C	acceptor_gain	1.0000
1:64838102:CCCC:C	acceptor_gain	1.0000
1:64838103:CC:C	acceptor_gain	1.0000
1:64838103:CCC:C	acceptor_gain	1.0000
1:64838104:CC:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000006140 (1:65064490 T>C), RS1000012500 (1:64909938 T>A), RS1000039832 (1:64925814 C>T), RS1000059876 (1:65008764 T>C), RS1000070566 (1:64874229 A>G), RS1000091358 (1:64850527 AC>A), RS1000099262 (1:64967249 G>A), RS1000128969 (1:64980059 G>A), RS1000141520 (1:65051693 CA>C,CAA), RS1000147909 (1:64910258 G>A,T), RS1000148217 (1:64864395 G>A), RS1000153018 (1:65039019 A>T), RS1000155102 (1:65029504 A>G), RS1000169679 (1:64892613 C>T), RS1000184007 (1:64855209 C>T)

Disease associations

OMIM: gene MIM:147795 | disease phenotypes: MIM:618999

GenCC curated gene-disease

Disease	Classification	Inheritance
autoinflammation, immune dysregulation, and eosinophilia	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autoinflammation, immune dysregulation, and eosinophilia	Definitive	AD

Mondo (3): autoinflammation, immune dysregulation, and eosinophilia (MONDO:0033558), autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial jak1 deficiency (MONDO:0035548), acute megakaryoblastic leukemia in down syndrome (MONDO:0020526)

Orphanet (2): Mendelian susceptibility to mycobacterial diseases due to partial JAK1 deficiency (Orphanet:574957), Acute megakaryoblastic leukemia in children with Down syndrome (Orphanet:99887)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000100	Nephrotic syndrome
HP:0000821	Hypothyroidism
HP:0001047	Atopic dermatitis
HP:0001407	Hepatic cysts
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001880	Increased total eosinophil count
HP:0002099	Asthma
HP:0004322	Short stature
HP:0004429	Recurrent viral infections
HP:0012578	Membranous nephropathy
HP:0031813	Colonic eosinophilia
HP:0032021	Eosinophilic liver infiltration
HP:0500093	Food allergy

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST004600_60	Eosinophil percentage of white cells	3.000000e-16
GCST004606_184	Eosinophil count	6.000000e-14
GCST004617_54	Eosinophil percentage of granulocytes	7.000000e-15
GCST004623_147	Neutrophil percentage of granulocytes	1.000000e-12
GCST004624_169	Sum eosinophil basophil counts	3.000000e-11
GCST004624_170	Sum eosinophil basophil counts	9.000000e-11
GCST007932_88	Medication use (thyroid preparations)	1.000000e-09
GCST008369_1	Plasma anti-thyroglobulin levels	1.000000e-07
GCST008369_8	Plasma anti-thyroglobulin levels	3.000000e-06
GCST008413_1498	Core binding factor acute myeloid leukemia	2.000000e-12
GCST009597_295	Multiple sclerosis	1.000000e-15
GCST010571_5	Autoimmune thyroid disease	5.000000e-10
GCST012170_14	Cognitive function in longevity	9.000000e-06
GCST90000025_926	Appendicular lean mass	3.000000e-25
GCST90002381_574	Eosinophil count	9.000000e-19
GCST90002381_575	Eosinophil count	6.000000e-27
GCST90002382_72	Eosinophil percentage of white cells	4.000000e-15
GCST90002382_73	Eosinophil percentage of white cells	5.000000e-36
GCST90002394_139	Monocyte percentage of white cells	8.000000e-15
GCST90002400_33	Plateletcrit	5.000000e-10
GCST90002402_551	Platelet count	2.000000e-10
GCST90013406_212	Liver enzyme levels (alkaline phosphatase)	2.000000e-14
GCST90026610_4	Bevacizumab-induced proteinuria	9.000000e-06

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0009933	Thyroid preparation use measurement
EFO:0008354	cognitive function measurement
EFO:0004980	appendicular lean mass
EFO:0007989	monocyte percentage of leukocytes
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004533	alkaline phosphatase measurement
EFO:0005943	response to bevacizumab

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL2363062 (PROTEIN FAMILY), CHEMBL2835 (SINGLE PROTEIN), CHEMBL3038491 (PROTEIN COMPLEX), CHEMBL3038492 (PROTEIN COMPLEX), CHEMBL3301390 (PROTEIN COMPLEX), CHEMBL3301391 (PROTEIN COMPLEX), CHEMBL4630751 (PROTEIN-PROTEIN INTERACTION), CHEMBL4742275 (PROTEIN-PROTEIN INTERACTION), CHEMBL5291972 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

68 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 176,729 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1795071	RUXOLITINIB PHOSPHATE	4	3,220
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL3137308	PEFICITINIB	4	1,722
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL3655081	ABROCITINIB	4	1,037
CHEMBL4085457	RITLECITINIB	4	708
CHEMBL4435170	DEUCRAVACITINIB	4	679
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4
CHEMBL3622820	ITACITINIB	3
CHEMBL4297477	BREPOCITINIB	3
CHEMBL4297507	DELGOCITINIB	3
CHEMBL4297865	ABIVERTINIB	3
CHEMBL5095079	POVORCITINIB	3
CHEMBL5095398	IVARMACITINIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL5314423	ZASOCITINIB	3
CHEMBL572881	MOTESANIB	3

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items; also 1 functional.

Variant	Therapy	Indication	Effect	Level	CIViC
JAK1 OVEREXPRESSION	Ruxolitinib	Sarcoma	Sensitivity/Response	CIViC C	EID7852
JAK1 Q503*	Pembrolizumab	Skin Melanoma	Resistance	CIViC C	EID1567
JAK1 OVEREXPRESSION	Enzastaurin	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID931
JAK1 S703I	Ruxolitinib	Hepatocellular Carcinoma	Sensitivity/Response	CIViC D	EID1900

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs72675451	JAK1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Janus kinase (JakA) family

Most potent curated ligand interactions (61 total), top 25:

Ligand	Action	Affinity	Parameter
nezulcitinib	Inhibition	10.2	pKi
ruxolitinib	Inhibition	10.05	pIC50
izencitinib	Inhibition	10.0	pKi
GDC-0214	Inhibition	9.59	pKi
lorpucitinib	Inhibition	9.4	pIC50
deucravacitinib	Inhibition	9.0	pIC50
ivarmacitinib	Inhibition	8.7	pIC50
PF-06263276	Inhibition	8.66	pIC50
delgocitinib	Inhibition	8.55	pIC50
londamocitinib	Inhibition	8.52	pIC50
blovacitinib	Inhibition	8.52	pIC50
AZD1480	Inhibition	8.52	pIC50
compound 19a [PMID: 24359159]	Inhibition	8.52	pIC50
JAK inhibitor 20a	Inhibition	8.47	pIC50
peficitinib	Inhibition	8.4	pIC50
itacitinib	Inhibition	8.3	pIC50
LASW1393	Inhibition	8.26	pIC50
compound 25ap [PMID: 37796543]	Inhibition	8.24	pIC50
zemprocitinib	Inhibition	8.23	pIC50
baricitinib	Inhibition	8.23	pIC50
solcitinib	Inhibition	8.18	pIC50
PF-956980	Inhibition	8.12	pIC50
compound 8l [PMID: 36053746]	Inhibition	8.05	pIC50
SJ988497	Binding	8.03	pKd
oclacitinib	Inhibition	8.02	pIC50

Binding affinities (BindingDB)

5514 measured of 6099 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-methyl-N-[4-[[3-(2-methylpropoxy)piperidin-1-yl]sulfonylmethyl]cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	IC50	0.00133 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
N-[4-[[3-(2-methoxyethoxy)piperidin-1-yl]sulfonylmethyl]cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine	IC50	0.00125 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
[(3R,4R)-4-methyl-1-[[4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]methylsulfonyl]pyrrolidin-3-yl]methanol	IC50	0.00199 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
US20260001898, Example A1	KD	0.004 nM	US-20260001898: Heteroaryl compounds as inhibitors of TYK2/JAK1, composition and application thereof
[(3S)-1-[[(1S,3R,4S)-3-methyl-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]methylsulfonyl]pyrrolidin-3-yl]methanol	IC50	0.00508 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
3-methyl-1-[[4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]methylsulfonyl]pyrrolidin-3-ol	IC50	0.00777 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
2,2,2-trifluoroethyl 4-[4-carbamoyl-3-[[6-(1H-pyrazol-4-yl)-3-pyridinyl]amino]pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate	IC50	0.01 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[1-(cyanomethyl)-4-(2,2,2-trifluoroethylamino)cyclohexyl]-3-[4-(difluoromethylsulfonyl)anilino]pyrazole-4-carboxamide	IC50	0.02 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
[(3R)-1-[[4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]methylsulfonyl]piperidin-3-yl] 2,2-dimethylpropanoate	IC50	0.0227 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
diethyl [(3R)-1-[[4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]methylsulfonyl]piperidin-3-yl] phosphate	IC50	0.0235 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
N-methyl-N-[4-[(4-methylpiperazin-1-yl)sulfonylmethyl]cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	IC50	0.0245 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
[(3R)-1-[[4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]methylsulfonyl]piperidin-3-yl] dihydrogen phosphate	IC50	0.0263 nM	US-8633206: Pyrrolo[2,3-D]pyrimidine compounds
US9328099, 40-63	IC50	0.03 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
2,2,2-trifluoroethyl 4-[4-carbamoyl-3-[[6-(1-methylpyrazol-4-yl)-3-pyridinyl]amino]pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate	IC50	0.03 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[1-(cyanomethyl)-4-(2,4-difluoroanilino)cyclohexyl]-3-[(2-fluoro-4-pyridinyl)amino]pyrazole-4-carboxamide	IC50	0.03 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[4-[(2-chlorophenyl)methylamino]-1-(cyanomethyl)cyclohexyl]-3-[(2-fluoro-4-pyridinyl)amino]pyrazole-4-carboxamide	IC50	0.03 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
2,2-difluoroethyl (3S,4S)-4-[4-carbamoyl-3-[(2-fluoro-4-pyridinyl)amino]pyrazol-1-yl]-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate	IC50	0.03 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-[(2S)-1,1-difluoro-2-hydroxypropan-2-yl]anilino]pyrazole-4-carboxamide	IC50	0.03 nM	US-9394282: Pyrazole carboxamides as Janus kinase inhibitors
1-[(1S,2S,4R)-4-(azetidin-1-yl)-2-cyanocyclohexyl]-3-[4-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]anilino]pyrazole-4-carboxamide	IC50	0.04 nM	US-8962608: Cycloalkylnitrile pyrazole carboxamides as janus kinase inhibitors
1-[4-(cyanomethyl)-1-[(3-hydroxyphenyl)methyl]piperidin-4-yl]-3-[(2-fluoro-4-pyridinyl)amino]pyrazole-4-carboxamide	IC50	0.04 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[1-(cyanomethyl)-4-(2-fluoroanilino)cyclohexyl]-3-[(2-fluoro-4-pyridinyl)amino]pyrazole-4-carboxamide	IC50	0.04 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[1-(cyanomethyl)-4-(2,2-difluoroethylamino)cyclohexyl]-3-[4-(difluoromethylsulfonyl)anilino]pyrazole-4-carboxamide	IC50	0.04 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-(4-fluoroanilino)pyrazole-4-carboxamide	IC50	0.04 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
US9328099, 40-64	IC50	0.05 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
tert-butyl (3R,4R)-4-[4-carbamoyl-3-(4-fluoroanilino)pyrazol-1-yl]-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate	IC50	0.05 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[4-anilino-1-(cyanomethyl)cyclohexyl]-3-[4-(difluoromethylsulfonyl)anilino]pyrazole-4-carboxamide	IC50	0.05 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[(3S,4S)-4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl]-3-[(6-fluoro-3-pyridinyl)amino]pyrazole-4-carboxamide	IC50	0.05 nM	US-9328099: Cyanomethylpyrazole carboxamides as janus kinase inhibitors
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-[(2R)-1,1-difluoro-2-hydroxypropan-2-yl]anilino]pyrazole-4-carboxamide	IC50	0.05 nM	US-9394282: Pyrazole carboxamides as Janus kinase inhibitors
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-(dimethylcarbamoyl)anilino]pyrazole-4-carboxamide	IC50	0.05 nM	US-9394282: Pyrazole carboxamides as Janus kinase inhibitors
(S)-(3-(dimethylamino)-3-methylazetidin-1-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-5-propyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone	KI	0.05 nM	US-10196393: JAK inhibitors containing a 4-membered heterocyclic amide
BDBM431910	KI	0.05 nM	US-10196393: JAK inhibitors containing a 4-membered heterocyclic amide
US10196393, Example 8-20	KI	0.05 nM	US-10196393: JAK inhibitors containing a 4-membered heterocyclic amide
(S)-(3-(dimethylamino)-3-methylazetidin-1-yl)(5-ethyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone	KI	0.05 nM	US-10196393: JAK inhibitors containing a 4-membered heterocyclic amide
6-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]amino]pyridine-3-sulfonamide	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
2-fluoro-4-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]amino]benzonitrile	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
4-[(3R)-3-[methyl(methylsulfamoyl)amino]pyrrolidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
2-cyano-N-methyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]acetamide	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
3-(3-cyanophenyl)-1-methyl-1-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]urea	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
3-(2,6-dichlorophenyl)-N-methyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]propanamide	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
1-methyl-1-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]-3-[4-(trifluoromethyl)phenyl]urea	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
3-(4-chlorophenyl)-1-methyl-1-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]urea	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
1-methyl-3-(oxan-4-yl)-1-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]urea	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
N-methyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]pyrrolidine-1-carboxamide	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
2-methoxy-6-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]amino]pyridine-3-carbonitrile	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
5-chloro-N-methyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]pyridin-2-amine	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
5-bromo-N-methyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]pyridin-2-amine	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
N,4-dimethyl-5-nitro-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]pyridin-2-amine	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
6,7-dimethoxy-N-methyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]quinazolin-4-amine	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
4-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]amino]benzonitrile	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof
2,6-difluoro-4-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]amino]benzonitrile	IC50	0.055 nM	US-9346810: Pyrrolopyrimidine compounds and uses thereof

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL3896068
11.00	IC50	0.01	nM	CHEMBL5945428
10.96	IC50	0.011	nM	CHEMBL5942656
10.96	IC50	0.011	nM	CHEMBL6031741
10.96	IC50	0.011	nM	CHEMBL5934018
10.96	IC50	0.011	nM	CHEMBL6017191
10.96	IC50	0.011	nM	CHEMBL5825020
10.96	IC50	0.011	nM	CHEMBL5794903
10.96	IC50	0.011	nM	CHEMBL5890561
10.92	IC50	0.012	nM	CHEMBL6059683
10.92	IC50	0.012	nM	CHEMBL5981552
10.92	IC50	0.012	nM	CHEMBL5956808
10.92	IC50	0.012	nM	CHEMBL5968969
10.92	IC50	0.012	nM	CHEMBL6064726
10.92	IC50	0.012	nM	CHEMBL6001979
10.92	IC50	0.012	nM	CHEMBL5934018
10.89	IC50	0.013	nM	CHEMBL6020772
10.89	IC50	0.013	nM	CHEMBL5931590
10.89	IC50	0.013	nM	CHEMBL5950639
10.89	IC50	0.013	nM	CHEMBL6029174
10.89	IC50	0.013	nM	CHEMBL5933670
10.89	IC50	0.013	nM	CHEMBL5921646
10.85	IC50	0.014	nM	CHEMBL6065435
10.85	IC50	0.014	nM	CHEMBL5883265
10.85	IC50	0.014	nM	CHEMBL5959152
10.82	IC50	0.015	nM	CHEMBL5941947
10.82	IC50	0.015	nM	CHEMBL5777052
10.82	IC50	0.015	nM	CHEMBL5784853
10.82	IC50	0.015	nM	CHEMBL5749084
10.77	IC50	0.017	nM	CHEMBL5890407
10.77	IC50	0.017	nM	CHEMBL5822545
10.77	IC50	0.017	nM	CHEMBL5938470
10.74	IC50	0.018	nM	CHEMBL6052369
10.74	IC50	0.018	nM	CHEMBL5901815
10.74	IC50	0.018	nM	CHEMBL5885656
10.72	IC50	0.019	nM	CHEMBL6021211
10.72	IC50	0.019	nM	CHEMBL5929524
10.72	IC50	0.019	nM	CHEMBL5841023
10.72	IC50	0.019	nM	CHEMBL5876263
10.70	IC50	0.02	nM	CHEMBL3947540
10.70	IC50	0.02	nM	CHEMBL4078799
10.70	IC50	0.02	nM	CHEMBL5772180
10.66	IC50	0.022	nM	CHEMBL5765697
10.66	IC50	0.022	nM	CHEMBL6049702
10.64	IC50	0.0227	nM	CHEMBL3652403
10.63	IC50	0.0235	nM	CHEMBL3652409
10.61	IC50	0.0245	nM	CHEMBL3652405
10.60	IC50	0.025	nM	CHEMBL5969229
10.58	IC50	0.0263	nM	CHEMBL3652410
10.57	IC50	0.027	nM	CHEMBL5826986

PubChem BioAssay actives

3299 with measured affinity, of 5780 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[[(3S)-3-methyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	<0.0001	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-(1-methylpyrazol-4-yl)anilino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	<0.0001	uM
N-methyl-4-[[(2S,4S)-2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide	2023852: Inhibition of recombinant JAK1 (unknown origin) using GFP-STAT1 as substrate incubated for 1 hr by TR-FRET Lanthascreen assay	ic50	<0.0001	uM
3-[(1R,5S)-3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]-8-azabicyclo[3.2.1]octan-8-yl]propanenitrile	2066936: Inhibition of human recombinant JAK1	ki	0.0001	uM
N-[5-[5-bromo-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0001	uM
N-[5-[2-(difluoromethoxy)-5-methylsulfanylphenyl]-1H-pyrazol-4-yl]imidazo[1,2-b]pyridazine-3-carboxamide	1934117: Binding affinity to human recombinant JAK1 assessed as inhibition constant incubated for 30 mins by microtiter plate reader analysis	ki	0.0001	uM
3-(4-chloro-3-methoxyanilino)-1-[(3R,4S)-4-cyanooxan-3-yl]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
N-(2-cyanoethyl)-2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]acetamide	1605635: Inhibition of JAK1-JH1/JH2 domain (574 to 1154 residues) (unknown origin) pre-incubated before NH2-KGGEEEEYFELVKK-CO2 substrate addition and measured after 90 mins by MS analysis	ic50	0.0001	uM
3-(4-cyano-3-methoxyanilino)-1-[(3R,4S)-4-cyanooxan-3-yl]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
N-[5-[6-(difluoromethoxy)-1H-indazol-5-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0001	uM
N-[5-[2-(difluoromethoxy)-5-iodophenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0001	uM
4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one	1287923: Inhibition of JAK1 (unknown origin)	ic50	0.0001	uM
[2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl]-(4-fluorophenyl)methanone	1436131: Inhibition of GST tagged human recombinant JAK1 catalytic domain expressed in baculovirus using peptide substrate preincubated for 60 mins followed by substrate addition and measured after 60 mins by microfluidic assay	ic50	0.0001	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-(triazol-1-yl)anilino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-(difluoromethoxy)anilino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
2-[4-[4-[2-(4-morpholin-4-ylpiperidin-1-yl)-2-oxoethyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-3-yl]cyclohexyl]acetonitrile	1605635: Inhibition of JAK1-JH1/JH2 domain (574 to 1154 residues) (unknown origin) pre-incubated before NH2-KGGEEEEYFELVKK-CO2 substrate addition and measured after 90 mins by MS analysis	ic50	0.0001	uM
4-[[(2S,4S)-1-[(4-chlorophenyl)methyl]-2-methylpiperidin-4-yl]amino]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide	1708115: Inhibition of recombinant JAK1 (unknown origin) using GFP-STAT1 as substrate incubated for 1 hr followed by anti-pSTAT1 antibody addition and measured after 30 mins by Lanthascreen TR-FRET assay	ic50	0.0001	uM
N-[5-[5-chloro-2-(difluoromethoxy)-4-hydroxyphenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0001	uM
Ruxolitinib	2031085: Inhibition of JAK1 (unknown origin)	ic50	0.0001	uM
2-[4-[4-[(1R)-1-hydroxyethyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-3-yl]cyclohexyl]acetonitrile	750444: Inhibition of recombinant JAK1 (unknown origin) using Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr as substrate after 30 mins in presence of ATP	ki	0.0001	uM
3-(4-cyanoanilino)-1-[(3R,4S)-4-cyanooxan-3-yl]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[4-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]anilino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
3-(4-chloroanilino)-1-[(3R,4S)-4-cyanooxan-3-yl]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0001	uM
N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0002	uM
2-amino-N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0002	uM
(3R)-1-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxamide	1851249: Inhibition of JAK1 (unknown origin)	ic50	0.0002	uM
N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]imidazo[1,2-b]pyridazine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0002	uM
2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]-N-(2-cyano-2-methylpropyl)acetamide	1605635: Inhibition of JAK1-JH1/JH2 domain (574 to 1154 residues) (unknown origin) pre-incubated before NH2-KGGEEEEYFELVKK-CO2 substrate addition and measured after 90 mins by MS analysis	ic50	0.0002	uM
Deucravacitinib	2011265: Binding affinity to JAK1 JH2 (unknown origin) assessed as dissociation constant	kd	0.0002	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[(8-fluoro-4-methoxyquinolin-6-yl)amino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0002	uM
3-[(4-chloro-8-fluoroquinolin-6-yl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0002	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[(4-methylquinazolin-6-yl)amino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0002	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[[2-(dimethylamino)-6-fluoro-4-pyridinyl]amino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0002	uM
2-[4-[[5-chloro-4-[(2,5-difluorophenyl)methylamino]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol	1666677: Inhibition of JAK1 (unknown origin)	ic50	0.0002	uM
4-[[(2R,4R)-1-[(4-chlorophenyl)methyl]-2-methylpiperidin-4-yl]amino]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide	1708115: Inhibition of recombinant JAK1 (unknown origin) using GFP-STAT1 as substrate incubated for 1 hr followed by anti-pSTAT1 antibody addition and measured after 30 mins by Lanthascreen TR-FRET assay	ic50	0.0002	uM
4-[[(3S,4R)-1-(5-cyano-2-pyridinyl)-3-fluoropiperidin-4-yl]amino]-6-[(2-methylpyrimidin-4-yl)amino]pyridine-3-carboxamide	1629469: Inhibition of human JAK1 assessed as reduction in phosphorylation of Biotin-Lyn-Substrate-2 after 1 hr in presence of ATP by ELISA	ic50	0.0002	uM
N-[[3-[(1R,2R,4S)-2-bicyclo[2.2.1]heptanyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]methyl]methanesulfonamide	719414: Inhibition of JAK1 kinase domain assessed as phosphorylation of N-terminal 5-carboxyfluorescein-tagged Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr after 30 mins	ki	0.0002	uM
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-methylpyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0002	uM
2-[4-(4-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-3-yl)cyclohexyl]acetonitrile	1605635: Inhibition of JAK1-JH1/JH2 domain (574 to 1154 residues) (unknown origin) pre-incubated before NH2-KGGEEEEYFELVKK-CO2 substrate addition and measured after 90 mins by MS analysis	ic50	0.0002	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-[(2-fluoro-4-pyridinyl)amino]pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0002	uM
(3R)-N-(cyanomethyl)-1-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-3-carboxamide	1851249: Inhibition of JAK1 (unknown origin)	ic50	0.0003	uM
N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]-6-ethynylimidazo[1,2-b]pyridazine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0003	uM
2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]-N-[1-(2-methylpropyl)piperidin-4-yl]acetamide	1605635: Inhibition of JAK1-JH1/JH2 domain (574 to 1154 residues) (unknown origin) pre-incubated before NH2-KGGEEEEYFELVKK-CO2 substrate addition and measured after 90 mins by MS analysis	ic50	0.0003	uM
2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]-N-(2,2,2-trifluoroethyl)acetamide	1605635: Inhibition of JAK1-JH1/JH2 domain (574 to 1154 residues) (unknown origin) pre-incubated before NH2-KGGEEEEYFELVKK-CO2 substrate addition and measured after 90 mins by MS analysis	ic50	0.0003	uM
N-[5-[3-(difluoromethoxy)naphthalen-2-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0003	uM
3-(1H-benzimidazol-2-yl)-4-[[4-(ethylamino)cyclohexyl]amino]-1H-pyridin-2-one	1287923: Inhibition of JAK1 (unknown origin)	ic50	0.0003	uM
1-[(3R,4S)-4-cyanooxan-3-yl]-3-(4-fluoroanilino)pyrazole-4-carboxamide	1477818: Inhibition of GST-tagged recombinant human JAK1 catalytic domain expressed in baculovirus expression system using LCB-EQEDEPEGDYFEWLW-NH2 as substrate preincubated for 30 mins followed by ATP addition measured after 120 mins by HTRF assay	ic50	0.0003	uM
N-[5-(6-methoxy-1H-indazol-5-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0003	uM
N-[5-(5-chloro-4-hydroxy-2-methoxyphenyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1672513: Inhibition of recombinant human JAK1 (854 to 1154 residues) expressed in insect cells using Y1-B as substrate incubated for 30 mins by microfluidic mobility shift assay	ki	0.0003	uM
N-[4-[(6-methylsulfonyl-2-pyridinyl)amino]-5-pyridin-2-yl-2-pyridinyl]acetamide	2029557: Inhibition of JAK1 JH2 (unknown origin)	ic50	0.0003	uM

CTD chemical–gene interactions

102 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	6
sodium arsenite	decreases expression, decreases activity, decreases phosphorylation, increases abundance, increases expression (+3 more)	5
Quercetin	decreases expression, decreases phosphorylation, decreases reaction, increases phosphorylation	4
tofacitinib	decreases reaction, increases activity, increases phosphorylation, decreases activity	3
ruxolitinib	decreases activity, decreases reaction, increases phosphorylation	3
(+)-JQ1 compound	increases expression	3
Resveratrol	decreases expression, decreases phosphorylation	3
Arsenic Trioxide	decreases expression, decreases phosphorylation, decreases reaction, increases phosphorylation	3
Arsenic	decreases ubiquitination, increases phosphorylation, decreases expression, increases abundance	3
baricitinib	increases activity, increases phosphorylation, decreases activity, decreases reaction	2
bisphenol A	decreases expression, decreases methylation, increases methylation	2
methylselenic acid	affects expression, increases expression	2
trichostatin A	affects expression, increases expression	2
pervanadate	decreases phosphorylation, decreases reaction	2
2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one	decreases reaction, increases phosphorylation	2
Acetaminophen	decreases phosphorylation, increases expression	2
Lipopolysaccharides	affects activity, affects cotreatment, affects expression, affects reaction, decreases phosphorylation (+1 more)	2
Mercuric Chloride	decreases phosphorylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Rotenone	decreases reaction, increases activity, increases phosphorylation, decreases phosphorylation	2
Tretinoin	increases expression, decreases expression	2
Cadmium Chloride	decreases phosphorylation, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases methylation	1
upadacitinib	decreases expression	1
6-hydroxy-3-O-methylkaempferol 6-O-glucopyranoside	increases expression, increases reaction, increases phosphorylation, decreases reaction	1
CDM-3008	decreases phosphorylation, decreases reaction	1
tubocapsenolide A	decreases reaction, decreases expression, decreases phosphorylation	1
methylmercuric chloride	increases expression	1
salinomycin	decreases reaction, increases phosphorylation	1

ChEMBL screening assays

1502 unique, capped per target: 1428 binding, 49 functional, 24 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1218226	Binding	Inhibition of JAK-mediated interferon-gamma/anisomycin-induced Stat1 phosphorylation in human U937 cells by Phospho-Flow cytometry	High-content single-cell drug screening with phosphospecific flow cytometry. — Nat Chem Biol
CHEMBL4377379	ADMET	Inhibition of GST-fused recombinant human JAK1 catalytic domain (845-1142 residues) expressed in Sf9 cells in presence of 0.1 mM ATP	Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165. — J Med Chem
CHEMBL5209913	Functional	Affinity Phenotypic Cellular interaction (Flow Cytometry (STAT6 phosphorylation induced by IL-4 in THP-1 cells)) EUB0000626a JAK1	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

26 cell lines: 25 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0099	SNU-1	Cancer cell line	Male
CVCL_1406	MFE-296	Cancer cell line	Female
CVCL_A171	Ma-Mel-36	Cancer cell line	Female
CVCL_A188	Ma-Mel-53	Cancer cell line	Male
CVCL_A220	Ma-Mel-85	Cancer cell line	Male
CVCL_B8IY	Abcam HCT 116 JAK1 KO	Cancer cell line	Male
CVCL_B8XU	Abcam MCF-7 JAK1 KO	Cancer cell line	Female
CVCL_B9L9	Abcam A-549 JAK1 KO	Cancer cell line	Male
CVCL_C291	Ma-Mel-61a	Cancer cell line	Male
CVCL_C292	Ma-Mel-61b	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.