EIF2AK2

Summary

EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2, HGNC:9437) is a protein-coding gene on chromosome 2p22.2, encoding Interferon-induced, double-stranded RNA-activated protein kinase (P19525). IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection.

The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses.

Source: NCBI Gene 5610 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 269 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001135651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9437
Approved symbol	EIF2AK2
Name	eukaryotic translation initiation factor 2 alpha kinase 2
Location	2p22.2
Locus type	gene with protein product
Status	Approved
Aliases	PKR, PPP1R83
Ensembl gene	ENSG00000055332
Ensembl biotype	protein_coding
OMIM	176871
Entrez	5610

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 22 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000233057, ENST00000395127, ENST00000405334, ENST00000411537, ENST00000462861, ENST00000496059, ENST00000647926, ENST00000679507, ENST00000679979, ENST00000680273, ENST00000681329, ENST00000681463, ENST00000681507, ENST00000681516, ENST00000874613, ENST00000874614, ENST00000874615, ENST00000874616, ENST00000874617, ENST00000874618, ENST00000874619, ENST00000874620, ENST00000874621, ENST00000937454, ENST00000937455, ENST00000937456, ENST00000949528

RefSeq mRNA: 3 — MANE Select: NM_001135651 NM_001135651, NM_001135652, NM_002759

CCDS: CCDS1786, CCDS46259

Canonical transcript exons

ENST00000233057 — 17 exons

Exon	Start	End
ENSE00000397476	37119959	37120139
ENSE00000747411	37109194	37109295
ENSE00000747412	37114731	37114859
ENSE00000747486	37122506	37122664
ENSE00000747487	37126289	37126411
ENSE00000747488	37135484	37135546
ENSE00000747490	37136983	37137017
ENSE00000747498	37146853	37146973
ENSE00001411310	37148857	37149023
ENSE00001958053	37099210	37107395
ENSE00003474995	37107474	37107527
ENSE00003545205	37139631	37139757
ENSE00003597924	37141553	37141701
ENSE00003652835	37138509	37138585
ENSE00003667171	37138270	37138363
ENSE00003842539	37156908	37156980
ENSE00003915215	37147688	37147822

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 95.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3774 / max 485.3642, expressed in 1779 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27763	18.3352	1778
27761	0.5645	304
27764	0.3159	152
27762	0.1619	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	95.35	gold quality
buccal mucosa cell	CL:0002336	95.26	gold quality
choroid plexus epithelium	UBERON:0003911	94.62	gold quality
calcaneal tendon	UBERON:0003701	93.15	gold quality
endothelial cell	CL:0000115	92.83	gold quality
trigeminal ganglion	UBERON:0001675	92.03	gold quality
parietal pleura	UBERON:0002400	92.03	gold quality
entorhinal cortex	UBERON:0002728	91.76	gold quality
pleura	UBERON:0000977	91.68	gold quality
postcentral gyrus	UBERON:0002581	91.35	gold quality
visceral pleura	UBERON:0002401	91.09	gold quality
cauda epididymis	UBERON:0004360	91.07	gold quality
adrenal tissue	UBERON:0018303	90.37	gold quality
germinal epithelium of ovary	UBERON:0001304	90.34	gold quality
dorsal root ganglion	UBERON:0000044	90.28	gold quality
tendon	UBERON:0000043	90.25	gold quality
seminal vesicle	UBERON:0000998	90.22	gold quality
parietal lobe	UBERON:0001872	90.18	gold quality
caput epididymis	UBERON:0004358	90.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.96	gold quality
epithelium of nasopharynx	UBERON:0001951	89.93	gold quality
corpus epididymis	UBERON:0004359	89.91	gold quality
palpebral conjunctiva	UBERON:0001812	89.79	gold quality
monocyte	CL:0000576	89.35	gold quality
colonic epithelium	UBERON:0000397	89.31	gold quality
superior frontal gyrus	UBERON:0002661	89.25	gold quality
superficial temporal artery	UBERON:0001614	89.16	gold quality
endometrium	UBERON:0001295	89.04	gold quality
trabecular bone tissue	UBERON:0002483	89.01	gold quality
bronchial epithelial cell	CL:0002328	88.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.57

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CD4	Unknown
IRS2	Unknown

Upstream regulators (CollecTRI, top): ATF3, ATF4, DDIT3, E2F1, ESR1, IRF1, MYC, NFKB, RELA, SP1, SP3, STAT1, STAT2, TCF3, TP53

miRNA regulators (miRDB)

112 targeting EIF2AK2, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Literature-anchored findings (GeneRIF, showing 40)

• The mRNA of the translationally controlled tumor protein P23/TCTP is a highly structured RNA, which activates the dsRNA-dependent protein kinase PKR (TCTP PROTEIN) (PMID:11991642)
• IL-1beta and IL-10 interact with IFN-alpha to up- and down-regulate PKR gene expression, respectively, by modulating STAT1 activation induced by IFN-alpha (PMID:12051728)
• Protein kinase R (PKR) regulates double-stranded RNA induction of TNF-alpha but not IL-1 beta mRNA expression in airway epithelial cells. (PMID:12055262)
• PKR phosphorylates small delta antigen (PMID:12060652)
• PKR protein kinase phosphorylation and dimerization is controlled byt PP1C (PMID:12138106)
• PKR activated by direct binding in heparin-treated vascular smooth muscle cells (VSMCs)blocks G1- to S-phase transition. (PMID:12231563)
• The induction of anti-HIV CTL activity by p9-RNA could be mediated by PKR through NF-kappaB activation (PMID:12349906)
• PKR may assume multiple roles in modulating hepatitis C virus replication and protein synthesis (PMID:12368306)
• Us11 protein of herpes simplex virus type 1 can block PKR activation by PACT both in vitro and in vivo (PMID:12368348)
• The promoter-proximal KCS element of the PKR kinase gene enhances transcription irrespective of orientation and position relative to the ISRE element. (PMID:12396729)
• PRK activity is suppressed by HSP70 in cooperation with FANCC (PMID:12397061)
• PKR binds to ASK1 and is involved in apoptosis signalling pathways (PMID:12473108)
• PKR upregulation occurs at defined steps in cancer progression, probably as a cellular response to neoplasia (PMID:12483527)
• overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and inhibited apoptosis. Fanconi anemia lymphoblasts expressed low levels of NPM, which correlated with high ground-state activation of PKR and hypersensitivity to apoptotic cues (PMID:12882984)
• Polymorphisms in the interferon-inducible elF2alpha kinase gene is associated with outcome of hepatitis C virus infection (PMID:12944978)
• In contrast to nondemented controls, Alzheimer cases show prominent protein kinase PKR activation in association with neuritic plaques and pyramidal neurons in the hippocampus and neocortex. (PMID:13678666)
• PKR is overexpressed in hepatitis C virus related hepatocellular carcinoma. (PMID:14638359)
• viral-induced PKR activation may play a significant role in pathogenesis by mediating the host response to poliovirus encephalitis (PMID:14698665)
• PKR might play a role in ER stress-induced apoptosis and in Alzheimer’s disease. (PMID:14765129)
• Loss of PKR activity may contribute to the formation and/or maintenance of B-cell chronic lymphocytic leukemia (PMID:14961569)
• TRAF-PKR interaction model in which the C-terminal domain of TRAF binds to a predicted TRAF interaction motif present in the PKR kinase domain. (PMID:15121867)
• level of PKR reduced in hepatocellular carcinoma tumor tissues, suggesting a role in promoting tumor growth; hepatitis B virus may participate in altering the level of PKR, but other factors should play a more determining role in regulation of PKR in HCC (PMID:15122791)
• Inappropriaate activation of PKR may cause mutations in fanconi anemia proteins. (PMID:15299030)
• upregulated in liver and PMBCs of chronic hepatitis C patients, and nonresponsivenes to IFN-alpha treatment is associated with this upregulation. The PKR gene response to exogenous IFN was similar in responders and non-responders in PBMCs. (PMID:15535414)
• phosphyorylation inhibited by Epstein-Barr virus BILF1 protein (PMID:15596837)
• first detection of a mutation in the RNA-binding domains of PKR gene from tumor cells taken directly from patients (PMID:15607693)
• double-stranded RNA-dependent protein kinase/eukaryotic initiation factor-2alpha has a role in okadaic acid-induced apoptosis in human osteoblastic MG63 cells (PMID:15625311)
• results support the hypothesis that PKR phosphorylation of Tat may be important for its function in HIV-1 LTR transactivation (PMID:15737233)
• hepatocarcinoma core positive cells are characterized by a significant PKR phosphorylation in Thr 446 residue, which leads deregulation of mitosis (PMID:15880455)
• PKR may play a critical role in mediating the subversive effects of HIV Tat resulting in IL-10 induction (PMID:15907845)
• Hepatitis c virus polyprotein expression caused a severe cytopathological effect in human cells as a result of inhibition of protein synthesis and apoptosis induction, triggered by the activation of the IFN-induced enzymes PKR and RNase L systems. (PMID:16156900)
• results do not support the concept of PKR as a tumor suppressor in small-size peripheral adenocarcinomas of the lung (PMID:16271080)
• in the absence of IFN treatment, activation of PKR basal expression is mediated by Sp1 and Sp3 proteins in a cooperative manner (PMID:16339759)
• HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway (PMID:16446363)
• We demonstrated that the direct binding of the influenza A virus NS1A protein to the N-terminal 230 amino acid region of PKR inhibits PKR activation by PACT and dsRNA (PMID:16466763)
• interaction between PKR and dsRNAs represents a crucial host cell defense mechanism against viral infection (PMID:16580685)
• These observations suggest a model for PKR activation upon binding of dsRNA or PACT. (PMID:16785445)
• RAX may function as a negative regulator of growth that is required to activate PKR in response to a broad range of apoptosis-inducing stress. (PMID:16861340)
• DRBP-120 is a double-stranded RNA (dsRNA)-binding protein, and it was detected in both the cytoplasm and the nucleus of HeLa cells associated with PKR. (PMID:16861808)
• PKR differentially regulates TNF signaling; IKK, Akt and JNK were positively regulated, whereas p44/p42 MAPK and p38 MAPK were negatively regulated. (PMID:16924232)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Eif2ak2	ENSMUSG00000024079
rattus_norvegicus	Eif2ak2	ENSRNOG00000048315
drosophila_melanogaster	Wee1	FBGN0011737

Paralogs (8): EIF2AK1 (ENSG00000086232), STK35 (ENSG00000125834), PKMYT1 (ENSG00000127564), EIF2AK4 (ENSG00000128829), WEE1 (ENSG00000166483), EIF2AK3 (ENSG00000172071), PDIK1L (ENSG00000175087), WEE2 (ENSG00000214102)

Protein

Protein identifiers

Interferon-induced, double-stranded RNA-activated protein kinase — P19525 (reviewed: P19525)

Alternative names: Eukaryotic translation initiation factor 2-alpha kinase 2, Interferon-inducible RNA-dependent protein kinase, P1/eIF-2A protein kinase, Protein kinase RNA-activated, Tyrosine-protein kinase EIF2AK2, p68 kinase

All UniProt accessions (5): A0A7P0TAL9, A0A7P0TBA9, A0A7P0Z4M0, B7ZKK7, P19525

UniProt curated annotations — full annotation on UniProt →

Function. IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection. Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at ‘Tyr-4’ upon DNA damage, facilitating its ubiquitination and proteasomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding pro-inflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at ‘Ser-312’ and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin.

Subunit / interactions. Homodimer. Interacts with STRBP. Interacts with DNAJC3. Forms a complex with FANCA, FANCC, FANCG and HSP70. Interacts with ADAR/ADAR1. Interacts with IRS1. The inactive form interacts with NCK1 and GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). Interacts with DHX9 (via N-terminus) and this interaction is dependent upon activation of the kinase. Interacts with EIF2S1/EIF-2ALPHA; this interaction induces a conformational change in EIF2S1 and its phosphorylation by EIF2AK2. Interacts with MBIP; the interaction is direct and leads to inhibition of EIF2AK2 self-activating autophosphorylation. Interacts with the molybdopterin synthase complex subunit MOCS2B; the interaction is direct and enhances the interaction between EIF2AK2 and MBIP. (Microbial infection) Interacts with human cytomegalovirus (HCMV) TRS1; this interaction retains EIF2AK2 to the nucleus and prevents its activation. (Microbial infection) Interacts with vaccinia virus protein K3 (K3L); this interaction inhibits EIF2AK2. (Microbial infection) Interacts with human herpes simplex virus 1 (HHV-1) protein US11 in an RNA-dependent manner. (Microbial infection) The inactive form interacts with Toscana virus (TOS) NSS. (Microbial infection) Interacts with herpes virus 8 protein v-IRF2; this interaction inhibits EIF2AK2 activation. (Microbial infection) Interacts with vaccinia protein E3. (Microbial infection) Interacts (via N-terminus) with Hepatitis C virus (HCV) mature core protein (via N-terminus); this interaction induces the autophosphorylation of EIF2AK2. (Microbial infection) Interacts with Hepatitis C virus (HCV) non-structural protein 5A (NS5A); this interaction leads to disruption of EIF2AK2 dimerization by NS5A. (Microbial infection) Interacts with Hepatitis C virus (HCV) envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks its inhibitory effect on protein synthesis and cell growth. (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2 phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation shutoff. (Microbial infection) Interacts with human herpesvirus 8 protein MTA/ORF57; this interaction inhibits stress granule formation.

Subcellular location. Cytoplasm. Nucleus. Perinuclear region.

Tissue specificity. Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas, and which correlates with tumor progression and invasiveness or risk of progression.

Post-translational modifications. Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation. Autophosphorylation is inhibited by the concerted action of ATAC complex subunit MBIP and molybdopterin synthase complex subunit MOCS2B.

Disease relevance. Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) [MIM:618877] An autosomal dominant disorder characterized by global developmental delay apparent in early childhood, cognitive impairment, ataxia, poor or absent speech with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, and abnormal involuntary movements. Affected individuals also exhibit neurological regression in the setting of febrile illness or infection. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities with poor myelination. The disease may be caused by variants affecting the gene represented in this entry. Dystonia 33 (DYT33) [MIM:619687] A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT33 is a slowly progressive form characterized by onset of focal or generalized dystonia in the first decades of life. Disease manifestations are variable. Some patients show ambulation difficulties, dysarthria, or dysphagia. Some affected individuals may manifest motor delay, lower limb spasticity, and mild developmental delay with intellectual disability. DYT33 penetrance is incomplete. Inheritance can be autosomal dominant or recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection. Can also be activated by heparin, pro-inflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the viral components HIV-1 Tat protein and large amounts of HIV-1 trans-activation response (TAR) RNA element as well as by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its proteasomal degradation. Inhibited by vaccinia virus protein E3, probably via dsRNA sequestering.

Domain organisation. Contains 2 dsRNA-binding domain (DRBM). The N-terminus contains the catalytic domain dimerization. The C-terminus binds EIF2S1/EIF2-alpha.

Induction. By type I interferons.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P19525-1	1	yes
P19525-2	2

RefSeq proteins (3): NP_001129123, NP_001129124, NP_002750 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR014720	dsRBD_dom	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR044452	EIF2AK2_DSRM_1	Domain
IPR044453	EIF2AK2_DSRM_2	Domain
IPR050339	CC_SR_Kinase	Family

Pfam: PF00035, PF00069

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (113 total): mutagenesis site 21, strand 18, helix 18, modified residue 15, sequence variant 15, region of interest 6, binding site 3, domain 3, sequence conflict 3, cross-link 2, repeat 2, turn 2, initiator methionine 1, chain 1, compositionally biased region 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
8BI7	X-RAY DIFFRACTION	1.4
7OBK	X-RAY DIFFRACTION	1.8
7OBL	X-RAY DIFFRACTION	1.8
8QEL	X-RAY DIFFRACTION	2.45
2A19	X-RAY DIFFRACTION	2.5
6D3K	X-RAY DIFFRACTION	2.6
2A1A	X-RAY DIFFRACTION	2.8
3UIU	X-RAY DIFFRACTION	2.9
6D3L	X-RAY DIFFRACTION	3.1
8I9J	ELECTRON MICROSCOPY	6.39
8IZN	ELECTRON MICROSCOPY	6.67
1QU6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19525-F1	77.52	0.47

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): 414 (proton acceptor)

Ligand- & substrate-binding residues (3): 273–281; 296; 432

Post-translational modifications (17): 2, 83, 88, 89, 90, 101, 162, 242, 255, 258, 293, 446, 451, 456, 542, 69, 159

Mutagenesis-validated functional residues (21):

Position	Phenotype
59–60	in fl-pkr-2ai; moderate loss of activity but no effect on dsrna binding.
60	impairs dsrna binding but not dimerization or activity.
67	significant loss of activity; loss of dsrna binding and dimerization.
83	no effect on enzymatic activity; when associated with a-88; a-89 and a-90.
88	no effect on enzymatic activity; when associated with a-83; a-89 and a-90.
89	no effect on enzymatic activity; when associated with a-83; a-88 and a-90.
90	no effect on enzymatic activity; when associated with a-83; a-88 and a-89.
149–150	in fl-pkr-2aii; no effect on activity.
242	moderate loss of activity; when associated with a-255 and a-258.
244–296	loss of activity.
255	moderate loss of activity; when associated with a-242 and a-255.
258	moderate loss of activity.
296	loss of activity.
446	significant loss of activity and impairs autophosphorylation of t-451.
451	loss of activity.
486	15-fold decrease in k3l binding affinity and thus resistance of mutated pkr to k3l inhibition.
489	loss of pkr inhibition by hcmv protein trs1.
496	no effect on pkr inhibition by hcmv protein trs1.
502	no effect on pkr inhibition by hcmv protein trs1.
510	no effect on pkr inhibition by hcmv protein trs1.
516	no effect on pkr inhibition by hcmv protein trs1.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-169131	Inhibition of PKR
R-HSA-4755510	SUMOylation of immune response proteins
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9833109	Evasion by RSV of host interferon responses
R-HSA-9833482	PKR-mediated signaling

MSigDB gene sets: 477 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, BIOCARTA_RNA_PATHWAY, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, BECKER_TAMOXIFEN_RESISTANCE_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, BIOCARTA_GSK3_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_TRANSLATIONAL_INITIATION

GO Biological Process (28): positive regulation of cytokine production (GO:0001819), translation (GO:0006412), regulation of translational initiation (GO:0006446), protein phosphorylation (GO:0006468), negative regulation of cell population proliferation (GO:0008285), response to virus (GO:0009615), negative regulation of translation (GO:0017148), endoplasmic reticulum unfolded protein response (GO:0030968), positive regulation of chemokine production (GO:0032722), positive regulation of stress-activated MAPK cascade (GO:0032874), negative regulation of osteoblast proliferation (GO:0033689), cellular response to amino acid starvation (GO:0034198), response to interferon-alpha (GO:0035455), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), negative regulation of viral genome replication (GO:0045071), protein autophosphorylation (GO:0046777), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), defense response to virus (GO:0051607), antiviral innate immune response (GO:0140374), regulation of NLRP3 inflammasome complex assembly (GO:1900225), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), regulation of hematopoietic progenitor cell differentiation (GO:1901532), regulation of hematopoietic stem cell proliferation (GO:1902033), regulation of hematopoietic stem cell differentiation (GO:1902036), immune system process (GO:0002376), translational initiation (GO:0006413), innate immune response (GO:0045087)

GO Molecular Function (15): RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), eukaryotic translation initiation factor 2alpha kinase activity (GO:0004694), non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), kinase activity (GO:0016301), protein phosphatase regulator activity (GO:0019888), identical protein binding (GO:0042802), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), ribosome (GO:0005840), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Antimicrobial mechanism of IFN-stimulated genes	2
NS1 Mediated Effects on Host Pathways	1
SUMO E3 ligases SUMOylate target proteins	1
Interferon Signaling	1
RSV-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein kinase activity	3
translational initiation	2
regulation of translation	2
cytoplasm	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
phosphorylation	1
protein modification process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
response to other organism	1
translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
positive regulation of cytokine production	1
chemokine production	1
regulation of chemokine production	1
regulation of stress-activated MAPK cascade	1
positive regulation of MAPK cascade	1
stress-activated MAPK cascade	1
positive regulation of stress-activated protein kinase signaling cascade	1
negative regulation of cell population proliferation	1
osteoblast proliferation	1
regulation of osteoblast proliferation	1
cellular response to starvation	1
response to amino acid starvation	1
response to cytokine	1

Protein interactions and networks

STRING

3740 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2AK2	EIF2S1	P05198	990
EIF2AK2	TRAF6	Q9Y4K3	928
EIF2AK2	PRKRA	O75569	925
EIF2AK2	DNAJC3	Q13217	919
EIF2AK2	RIGI	O95786	917
EIF2AK2	ATF6	P18850	906
EIF2AK2	RNASEL	Q05823	902
EIF2AK2	DICER1	Q9UPY3	902
EIF2AK2	IFIH1	Q9BYX4	892
EIF2AK2	MX1	P20591	876
EIF2AK2	HSPA5	P11021	869
EIF2AK2	ILF3	Q12906	865
EIF2AK2	NLRP3	Q96P20	857
EIF2AK2	OAS1	P00973	847
EIF2AK2	XBP1	P17861	844

IntAct

191 interactions, top by confidence:

A	B	Type	Score
N	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.820
EIF2AK2	N	psi-mi:“MI:0915”(physical association)	0.820
N	EIF2AK2	psi-mi:“MI:0914”(association)	0.820
PRKRA	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.800
EIF2S1	EIF2AK2	psi-mi:“MI:0407”(direct interaction)	0.780
EIF2AK2	EIF2S1	psi-mi:“MI:0217”(phosphorylation reaction)	0.780
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
EIF2AK2	EIF2S1	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ZNF346	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.710
EIF2AK2	DHX30	psi-mi:“MI:0915”(physical association)	0.710
EIF2AK2		psi-mi:“MI:0915”(physical association)	0.700
EIF2AK2		psi-mi:“MI:0217”(phosphorylation reaction)	0.700
EIF2AK2		psi-mi:“MI:0915”(physical association)	0.680
EIF2AK2		psi-mi:“MI:0403”(colocalization)	0.680
	EIF2AK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.680
EIF2AK2	OPG041	psi-mi:“MI:0407”(direct interaction)	0.670
OPG041	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.670
EIF2AK2	OPG041	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (589): EIF2AK2 (Phenotypic Suppression), EIF2AK2 (Synthetic Growth Defect), EIF2AK2 (Biochemical Activity), EIF2S1 (Biochemical Activity), TRAF2 (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS)

ESM2 similar proteins: A8WZ92, D3Z9Z9, G5EDT6, H2KZW3, O12990, O19064, O60674, O73630, O74536, O93530, P08458, P10721, P19525, P23458, P32865, P36582, P43481, P51813, P52332, P53355, Q01577, Q03963, Q04692, Q08156, Q0VD22, Q10056, Q12469, Q1RMT8, Q20085, Q28317, Q2QXC6, Q2RA93, Q4R8E0, Q54RB7, Q54Y55, Q5RB23, Q62120, Q62689, Q63184, Q6J5K9

Diamond homologs: A0A509AH51, A0QNG1, A3B529, A3LUB9, A5D791, A6ZU08, A7E3S4, A8X0C4, A8XSC1, D0Z5N4, D4A7V9, E2QWQ2, O19004, P00531, P00532, P04049, P04627, P05625, P07527, P0CS76, P0CS77, P10398, P11345, P14056, P17157, P19525, P27636, P32490, P33279, P34331, P38990, P41676, P43637, P50750, P52304, P53351, P54666, Q03957, Q03963, Q04770

SIGNOR signaling

45 interactions.

A	Effect	B	Mechanism
EIF2AK2	“up-regulates activity”	EIF2AK2	phosphorylation
EIF2AK2	down-regulates	EIF2S1	phosphorylation
RPS6KA3	up-regulates	EIF2AK2	phosphorylation
EIF2AK2	down-regulates	CDK1	phosphorylation
EIF2AK2	up-regulates	PPP2R5A	phosphorylation
DNAJC3	“down-regulates activity”	EIF2AK2	binding
“ISGF3 complex”	“up-regulates quantity by expression”	EIF2AK2	“transcriptional regulation”
EIF2AK2	up-regulates	Immune_response
Viral_dsRNA	up-regulates	EIF2AK2
EIF2AK2	“down-regulates activity”	EIF2S1	phosphorylation
“Uridylate-specific endoribonuclease”	“down-regulates activity”	EIF2AK2
G3BP1	“up-regulates activity”	EIF2AK2	binding
EIF2AK2	“up-regulates activity”	“NLRP1 inflammasome”	binding
EIF2AK2	“up-regulates activity”	“NLRP3 inflammasome”	binding
EIF2AK2	“up-regulates activity”	“AIM2 inflammasome”	binding
EIF2AK2	“up-regulates activity”	“NLRC4 inflammasome”	binding
ADARB1	“up-regulates activity”	EIF2AK2	binding
EIF2AK2	“down-regulates quantity by destabilization”	KDM4C	phosphorylation
EIF2AK2	“down-regulates activity”	IRS1	phosphorylation
EIF2AK2	“up-regulates activity”	SPHK1	phosphorylation
EIF2AK2	“down-regulates activity”	NCK1	phosphorylation
EIF2AK2	“up-regulates activity”	PA2G4	phosphorylation
EIF2AK2	“up-regulates activity”	STAT3	phosphorylation
EIF2AK2	“up-regulates activity”	MAP2K6	phosphorylation
EIF2AK2	“up-regulates quantity”	MAPT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
PKR-mediated signaling	11	14.1×	2e-07
Formation of the ternary complex, and subsequently, the 43S complex	7	13.7×	9e-05
Translation initiation complex formation	7	12.1×	2e-04
Ribosomal scanning and start codon recognition	7	12.1×	2e-04
rRNA processing in the nucleus and cytosol	7	10.2×	4e-04
Influenza Viral RNA Transcription and Replication	5	9.8×	4e-03
SARS-CoV-1-host interactions	6	9.6×	1e-03
rRNA processing	7	9.3×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
pre-miRNA processing	5	41.0×	6e-05
stress granule assembly	7	30.8×	3e-06
pyroptotic inflammatory response	5	18.6×	1e-03
mRNA transport	7	13.4×	3e-04
cytoplasmic translation	8	10.8×	3e-04
positive regulation of fibroblast proliferation	5	10.8×	7e-03
negative regulation of translation	7	10.0×	1e-03
ribosomal small subunit biogenesis	6	10.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	149
Likely benign	68
Benign	14

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4819276	NM_001135651.3(EIF2AK2):c.516+283_688-251del	Pathogenic
1174083	NM_001135651.3(EIF2AK2):c.452A>G (p.Gln151Arg)	Likely pathogenic
1332910	NM_001135651.3(EIF2AK2):c.388G>C (p.Gly130Arg)	Likely pathogenic

SpliceAI

2702 predictions. Top by Δscore:

Variant	Effect	Δscore
2:37107256:A:AC	donor_gain	1.0000
2:37107257:C:CC	donor_gain	1.0000
2:37107472:A:AC	donor_gain	1.0000
2:37107473:C:CC	donor_gain	1.0000
2:37107473:CTT:C	donor_gain	1.0000
2:37107475:T:TA	donor_gain	1.0000
2:37107528:C:CC	acceptor_gain	1.0000
2:37114855:CTTGG:C	acceptor_gain	1.0000
2:37119954:CTTA:C	donor_loss	1.0000
2:37119955:TTA:T	donor_loss	1.0000
2:37119956:TA:T	donor_loss	1.0000
2:37119957:A:AC	donor_gain	1.0000
2:37119958:C:CC	donor_gain	1.0000
2:37122501:GTTAC:G	donor_loss	1.0000
2:37122502:TTACC:T	donor_loss	1.0000
2:37122503:TACCT:T	donor_loss	1.0000
2:37122504:ACCTT:A	donor_loss	1.0000
2:37122505:C:CG	donor_loss	1.0000
2:37122661:CTTC:C	acceptor_gain	1.0000
2:37122663:TC:T	acceptor_gain	1.0000
2:37122664:CCTAG:C	acceptor_gain	1.0000
2:37122665:C:CC	acceptor_gain	1.0000
2:37122665:CT:C	acceptor_loss	1.0000
2:37122666:T:C	acceptor_loss	1.0000
2:37122669:T:C	acceptor_gain	1.0000
2:37122669:T:TC	acceptor_gain	1.0000
2:37135483:CCT:C	donor_gain	1.0000
2:37136978:CTCA:C	donor_loss	1.0000
2:37136981:ACCTT:A	donor_loss	1.0000
2:37137014:CATT:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000011081 (2:37127120 G>A,C), RS1000078528 (2:37129711 T>C), RS1000143525 (2:37143408 T>A,C), RS1000163044 (2:37120210 T>C), RS1000216544 (2:37158158 C>T), RS1000303784 (2:37124516 C>A), RS1000331494 (2:37152870 C>T), RS1000411827 (2:37135818 G>C), RS1000421058 (2:37119273 A>G), RS1000423598 (2:37142380 G>A,C), RS1000457593 (2:37157625 T>C), RS1000541690 (2:37119357 G>A), RS1000757526 (2:37120439 G>A), RS1000783171 (2:37152011 A>T), RS1000834460 (2:37157849 T>C,G)

Disease associations

OMIM: gene MIM:176871 | disease phenotypes: MIM:618877, MIM:619687

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome	Strong	Autosomal dominant
complex neurodevelopmental disorder	Strong	Autosomal dominant
early-onset generalized limb-onset dystonia	Supportive	Autosomal dominant
dystonia 33	Limited	Unknown

Mondo (4): leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (MONDO:0030035), dystonia 33 (MONDO:0030513), early-onset generalized limb-onset dystonia (MONDO:0007492), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000511	Vertical supranuclear gaze palsy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001608	Abnormality of the voice
HP:0001761	Pes cavus
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002067	Bradykinesia
HP:0002078	Truncal ataxia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002126	Polymicrogyria
HP:0002188	Delayed CNS myelination
HP:0002451	Limb dystonia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002726_26	Glucose homeostasis traits	2.000000e-06
GCST90002402_280	Platelet count	3.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538005	Dystonia musculorum deformans type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5785 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 290,824 (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
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL513909	BI-2536	2	895
CHEMBL558752	RAF-265	2	2,721
CHEMBL607707	PELITINIB	2	6,340
CHEMBL1908397	KW-2449	1	622
CHEMBL258805	SU-9516	1	76
CHEMBL494089	GSK-690693	1	2,061
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Other PEK family kinases

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
indirubin derivative E804	Inhibition	7.0	pIC50
PKR inhibitor	Inhibition	6.68	pIC50
Cdk2 inhibitor IV	Inhibition	5.7	pIC50

Binding affinities (BindingDB)

26 measured of 28 human assays (366 total across all organisms); most potent 26 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
1-[2-[2-amino-5-[2-(3-hydroxypropyl)tetrazol-5-yl]-3-pyridinyl]-1-benzothiophen-5-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	IC50	39 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
1-[2-[2-amino-5-[2-(3-hydroxypropyl)tetrazol-5-yl]-3-pyridinyl]-1-benzothiophen-5-yl]-3-[3,5-bis(trifluoromethyl)phenyl]urea	IC50	66 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
6-amino-5-[5-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-1-benzothiophen-2-yl]-N-[dimethyl(oxo)-lambda6-sulfanylidene]pyridine-3-carboxamide	IC50	69 nM	US-9868726: Pyridyl benzothiophenes as kinase inhibitors
1-[2-[2-amino-5-[2-(3-hydroxypropyl)tetrazol-5-yl]-3-pyridinyl]-1-benzothiophen-5-yl]-3-[3-fluoro-5-(trifluoromethyl)phenyl]urea	IC50	76 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
1-[2-[2-amino-5-[2-(2-hydroxyethyl)tetrazol-5-yl]-3-pyridinyl]-1-benzothiophen-5-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	IC50	82 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
1-[2-[2-amino-5-[2-(3-hydroxypropyl)tetrazol-5-yl]-3-pyridinyl]-1-benzothiophen-5-yl]-3-[4-fluoro-3-(trifluoromethyl)phenyl]urea	IC50	99 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
1-[2-[2-amino-5-(2H-tetrazol-5-yl)-3-pyridinyl]-1-benzothiophen-5-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	IC50	140 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
1-[3-[2-[2-amino-5-[2-(3-hydroxypropyl)tetrazol-5-yl]-3-pyridinyl]ethynyl]phenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	IC50	158 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
6-amino-N-[dimethyl(oxo)-lambda6-sulfanylidene]-5-[5-[[2-fluoro-5-(trifluoromethyl)phenyl]carbamoylamino]-1-benzothiophen-2-yl]pyridine-3-carboxamide	IC50	167 nM	US-9868726: Pyridyl benzothiophenes as kinase inhibitors
PKC-412	KD	190 nM
1-[2-(2-amino-5-pyrazin-2-yl-3-pyridinyl)-1-benzothiophen-5-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	IC50	301 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
5-[5-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-1-benzothiophen-2-yl]-N-[dimethyl(oxo)-lambda6-sulfanylidene]pyridine-3-carboxamide	IC50	390 nM	US-9868726: Pyridyl benzothiophenes as kinase inhibitors
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
N-[dimethyl(oxo)-lambda6-sulfanylidene]-5-[5-[[2-fluoro-5-(trifluoromethyl)phenyl]carbamoylamino]-1-benzothiophen-2-yl]pyridine-3-carboxamide	IC50	551 nM	US-9868726: Pyridyl benzothiophenes as kinase inhibitors
1-[2-(2-amino-5-pyrimidin-2-yl-3-pyridinyl)-1-benzothiophen-5-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	IC50	558 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-[5-(2H-tetrazol-5-yl)-3-pyridinyl]-1-benzothiophen-5-yl]urea	IC50	727 nM	US-10011593: Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	KD	4500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

126 potent at pChembl≥5 of 157 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.43	EC50	37	nM	CHEMBL5279578
7.41	Ki	39	nM	CHEMBL5793168
7.41	IC50	39	nM	CHEMBL5793168
7.18	Ki	66	nM	CHEMBL5995310
7.18	IC50	66	nM	CHEMBL5995310
7.16	IC50	69	nM	CHEMBL5783751
7.12	Ki	76	nM	CHEMBL5886368
7.12	IC50	76	nM	CHEMBL5886368
7.10	IC50	79	nM	CHEMBL5559304
7.09	Ki	82	nM	CHEMBL6062933
7.09	IC50	82	nM	CHEMBL6062933
7.02	EC50	95	nM	CHEMBL5286788
7.00	IC50	99	nM	CHEMBL2441346
7.00	Ki	99	nM	CHEMBL5755281
7.00	IC50	99	nM	CHEMBL5755281
7.00	IC50	100	nM	CHEMBL1802782
7.00	IC50	100	nM	CHEMBL1802629
6.94	IC50	116	nM	CHEMBL4281823
6.92	Kd	120	nM	CHEMBL2425628
6.92	Kd	120	nM	LESTAURTINIB
6.85	Ki	140	nM	CHEMBL6041111
6.85	IC50	140	nM	CHEMBL6041111
6.82	IC50	150	nM	CHEMBL1802778
6.80	Ki	158	nM	CHEMBL5819668
6.80	IC50	158	nM	CHEMBL5819668
6.78	IC50	167	nM	CHEMBL6029379
6.75	IC50	180	nM	CHEMBL5556210
6.75	Kd	180	nM	R-406
6.68	IC50	210	nM	CHEMBL4281823
6.60	IC50	250	nM	CHEMBL200381
6.60	IC50	250	nM	CHEMBL257167
6.54	IC50	291	nM	CHEMBL2171122
6.52	Ki	301	nM	CHEMBL6063521
6.52	IC50	301	nM	CHEMBL6063521
6.52	IC50	300	nM	CHEMBL1802769
6.51	IC50	306	nM	CHEMBL5271785
6.45	IC50	359	nM	CHEMBL2441342
6.44	IC50	364	nM	CHEMBL5266620
6.44	Kd	360	nM	STAUROSPORINE
6.41	IC50	390	nM	CHEMBL5854149
6.34	Kd	460	nM	BI-2536
6.32	IC50	475	nM	CHEMBL5267979
6.26	IC50	551	nM	CHEMBL5878808
6.25	Ki	558	nM	CHEMBL5788618
6.25	IC50	558	nM	CHEMBL5788618
6.22	IC50	600	nM	CHEMBL1802630
6.22	IC50	600	nM	6BIO
6.17	Kd	670	nM	SUNITINIB
6.16	IC50	696	nM	CHEMBL2171124
6.14	Ki	727	nM	CHEMBL5996070

PubChem BioAssay actives

96 with measured affinity, of 487 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-[5-(4-amino-7-ethylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[2-ethyl-5-(trifluoromethoxy)phenyl]ethanone	1922266: Inhibition of PKR (unknown origin)	ec50	0.0370	uM
N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-[2-(3,5-dimethoxyanilino)pyrimidin-4-yl]-1-methylpyrazole-5-carboxamide	2075964: Inhibition of PKR (unknown origin)	ic50	0.0790	uM
1-[5-(4-amino-1-ethylpyrazolo[3,4-d]pyrimidin-3-yl)-2,3-dihydroindol-1-yl]-2-[2-ethyl-5-(trifluoromethoxy)phenyl]ethanone	1922266: Inhibition of PKR (unknown origin)	ec50	0.0950	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-(3,5-dimethylpyrazol-1-yl)ethanone	777369: Inhibition of PKR (unknown origin) assessed as EIF2AK2 phosphorylation	ic50	0.0990	uM
(2Z)-2-(3H-1,3-benzothiazol-2-ylidene)-2-[2-(2-pyridin-3-ylethylamino)pyrimidin-4-yl]acetonitrile	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
4-[(E)-[2-(2-hydroxy-1H-indol-3-yl)indol-3-ylidene]amino]oxybutane-1,2-diol	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
8-hydroxy-2,4,9,19-tetrazapentacyclo[10.7.0.02,6.07,11.013,18]nonadeca-1(19),3,5,7,11,13,15,17-octaen-10-one	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
11-oxo-3,10-diazapentacyclo[10.7.1.02,10.04,9.016,20]icosa-1(20),2,4,6,8,12,14,16,18-nonaene-17-carboxylic acid	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
3-(3-nitroso-1H-indol-2-yl)-1H-indol-2-ol	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
methyl (15R,16S,18S)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
4-(2-methyl-1H-indol-3-yl)-N-pyridin-3-ylpyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
4-(5-chloro-2-methyl-1H-indol-3-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1000	uM
1-[5-(4-amino-7-ethylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethoxy)phenyl]ethanone	1922266: Inhibition of PKR (unknown origin)	ic50	0.1160	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	508052: Binding affinity to PRKR	kd	0.1200	uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone	769498: Binding affinity to PRKR (unknown origin)	kd	0.1200	uM
N-(4-fluorophenyl)-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.1500	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624896: Binding constant for PRKR kinase domain	kd	0.1800	uM
6,6-dioxobenzo[c][1,2]benzoxathiine-1,2,3,8,9-pentol	2075045: Inhibition of PKR (unknown origin)	ic50	0.1800	uM
4-(3-chloro-4-fluoroanilino)-6-(pyridin-3-ylmethylamino)-1,7-naphthyridine-3-carbonitrile	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.2500	uM
2-(carbamoylamino)-5-(4-fluorophenyl)thiophene-3-carboxamide	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.2500	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-chlorophenyl)ethanone	702105: Inhibition of PKR assessed as EIF2AK2 phosphorylation	ic50	0.2910	uM
N-(3-chlorophenyl)-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.3000	uM
1-[4-[4-amino-7-[1-(2-oxopropyl)pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl]phenyl]-3-(3-methylphenyl)urea	1922266: Inhibition of PKR (unknown origin)	ic50	0.3060	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-[6-(trifluoromethyl)-2-pyridinyl]ethanone	777369: Inhibition of PKR (unknown origin) assessed as EIF2AK2 phosphorylation	ic50	0.3590	uM
N-[4-[4-amino-1-[4-(2-methoxyethoxy)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-5-chloro-7-fluoro-1,3-benzoxazol-2-amine	1922266: Inhibition of PKR (unknown origin)	ic50	0.3640	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	624896: Binding constant for PRKR kinase domain	kd	0.4600	uM
1-[2-[2-amino-5-[2-(3-hydroxypropyl)tetrazol-5-yl]-3-pyridinyl]-1-benzofuran-5-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea	1922267: Inhibition of GST tagged human PKR incubated for 10 mins in presence of ATP by Kinase Glo luminescence assay	ic50	0.4750	uM
6-bromo-3-(3-nitroso-1H-indol-2-yl)-1H-indol-2-ol	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.6000	uM
N-(4-chlorophenyl)-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.6000	uM
Sunitinib	435555: Binding constant for PRKR kinase domain	kd	0.6700	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone	702105: Inhibition of PKR assessed as EIF2AK2 phosphorylation	ic50	0.6960	uM
28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	0.7500	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-(6-methyl-2-pyridinyl)ethanone	777369: Inhibition of PKR (unknown origin) assessed as EIF2AK2 phosphorylation	ic50	0.9050	uM
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	435555: Binding constant for PRKR kinase domain	kd	0.9500	uM
1-[5-[4-amino-7-(1-methylpyrazol-4-yl)thieno[3,2-c]pyridin-3-yl]-2,3-dihydroindol-1-yl]-2-phenylethanone	702105: Inhibition of PKR assessed as EIF2AK2 phosphorylation	ic50	0.9780	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435555: Binding constant for PRKR kinase domain	kd	1.1000	uM
Crizotinib	624896: Binding constant for PRKR kinase domain	kd	1.1000	uM
Fedratinib	624896: Binding constant for PRKR kinase domain	kd	1.1000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435555: Binding constant for PRKR kinase domain	kd	1.3000	uM
Erlotinib	435555: Binding constant for PRKR kinase domain	kd	1.3000	uM
N-(3,4-difluorophenyl)-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	1.5000	uM
N-cyclopentyl-4-(5-methoxy-2-methyl-1H-indol-3-yl)pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	1.5000	uM
N-(3-methoxypropyl)-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-amine	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	1.5000	uM
5-amino-N-(2,6-difluorophenyl)-3-(4-sulfamoylanilino)-1,2,4-triazole-1-carbothioamide	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	1.6000	uM
Pazopanib	435555: Binding constant for PRKR kinase domain	kd	1.9000	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide	508052: Binding affinity to PRKR	kd	1.9000	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	435555: Binding constant for PRKR kinase domain	kd	1.9000	uM
4-[[6-(cyclohexylmethoxy)-7H-purin-2-yl]amino]-N,N-diethylbenzamide	606664: Inhibition of human recombinant PKR autophosphorylation using poly[I:C] after 10 mins by luminescent assay	ic50	2.0000	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	624896: Binding constant for PRKR kinase domain	kd	2.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects expression, increases phosphorylation, affects response to substance, increases secretion, decreases reaction (+4 more)	5
GW 506033X	decreases reaction, increases expression, decreases activity, affects binding	3
bisphenol A	decreases expression, decreases methylation	3
sodium arsenite	decreases expression, increases expression	3
Poly I-C	increases phosphorylation, increases expression	3
Valproic Acid	affects expression, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Doxorubicin	decreases expression, affects binding, increases reaction	2
Plant Extracts	affects expression, affects reaction, affects cotreatment, increases expression	2
2-Aminopurine	decreases reaction, decreases response to substance, increases expression, decreases activity, decreases phosphorylation	2
FR900359	decreases phosphorylation	1
6-hydroxy-3-O-methylkaempferol 6-O-glucopyranoside	increases expression, increases reaction	1
parthenolide	decreases expression	1
testosterone enanthate	affects expression	1
deoxynivalenol	increases activity, increases expression, affects reaction	1
pyrimidin-2-one beta-ribofuranoside	decreases response to substance, decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
7,7’-dimethoxy-(4,4’-bi-1,3-benzodioxole)-5,5’-dicarboxylic acid dimethyl ester	increases expression	1
nitazoxanide	increases activity, increases phosphorylation, increases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
CGP 52608	increases reaction, affects binding	1
abrine	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1

ChEMBL screening assays

213 unique, capped per target: 213 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037130	Binding	Residual activity of EIF2AK2 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

12 cell lines: 8 cancer cell line, 3 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1F6	Abcam A-549 EIF2AK2 KO 1	Cancer cell line	Male
CVCL_B1QV	Abcam HeLa EIF2AK2 KO	Cancer cell line	Female
CVCL_B2MQ	Abcam A-549 EIF2AK2 KO 2	Cancer cell line	Male
CVCL_D5I8	HepG2-DP	Cancer cell line	Male
CVCL_D9E6	Ubigene HEK293 EIF2AK2 KO	Transformed cell line	Female
CVCL_E0CH	Ubigene HeLa EIF2AK2 KO	Cancer cell line	Female
CVCL_E1IU	HyCyte A-549 KO-hEIF2AK2	Cancer cell line	Male
CVCL_E7KI	KOLF2.1J EIF2AK2 A109V SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7KJ	KOLF2.1J EIF2AK2 A109V SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7NF	KOLF2.1J EIF2AK2 44kbdel DEL/DEL	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01435681	Not specified	COMPLETED	Can Short Latency Afferent Inhibition Give us Clues to Better DYT 1 Dystonia Treatments?
NCT07168850	Not specified	RECRUITING	Focused Ultrasound Unilateral Pallidotomy for Medication-Refractory Limb Dystonia
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder