EIF2AK1

Summary

EIF2AK1 (eukaryotic translation initiation factor 2 alpha kinase 1, HGNC:24921) is a protein-coding gene on chromosome 7p22.1, encoding Eukaryotic translation initiation factor 2-alpha kinase 1 (Q9BQI3). Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions.

The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27102 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 294 total — 3 pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24921
Approved symbol	EIF2AK1
Name	eukaryotic translation initiation factor 2 alpha kinase 1
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	HRI, KIAA1369, hHRI, HCR
Ensembl gene	ENSG00000086232
Ensembl biotype	protein_coding
OMIM	613635
Entrez	27102

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 21 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000199389, ENST00000422786, ENST00000431744, ENST00000446699, ENST00000461493, ENST00000463213, ENST00000470168, ENST00000474029, ENST00000490523, ENST00000495565, ENST00000858513, ENST00000858514, ENST00000858515, ENST00000858516, ENST00000858517, ENST00000858518, ENST00000858519, ENST00000858520, ENST00000858521, ENST00000858522, ENST00000858523, ENST00000858524, ENST00000858525, ENST00000858526, ENST00000858527, ENST00000858528, ENST00000858529, ENST00000971157

RefSeq mRNA: 2 — MANE Select: NM_014413 NM_001134335, NM_014413

CCDS: CCDS5345

Canonical transcript exons

ENST00000199389 — 15 exons

Exon	Start	End
ENSE00000547861	6040892	6041219
ENSE00000669187	6038560	6038671
ENSE00000669188	6037424	6037524
ENSE00000669190	6028918	6029032
ENSE00000669192	6028615	6028697
ENSE00001085181	6022247	6024801
ENSE00001634941	6058966	6059175
ENSE00003459921	6054546	6054704
ENSE00003480046	6046071	6046151
ENSE00003519961	6026728	6026961
ENSE00003540513	6044562	6044661
ENSE00003575453	6048807	6048844
ENSE00003649839	6046992	6047091
ENSE00003670622	6042933	6042993
ENSE00003676603	6049912	6050045

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 120.7509 / max 1846.5414, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82628	115.3583	1827
82627	4.7777	1548
82624	0.4782	234
82625	0.1367	84

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	98.04	gold quality
monocyte	CL:0000576	97.04	gold quality
mononuclear cell	CL:0000842	97.02	gold quality
leukocyte	CL:0000738	96.86	gold quality
parotid gland	UBERON:0001831	96.86	gold quality
islet of Langerhans	UBERON:0000006	96.37	gold quality
ventricular zone	UBERON:0003053	96.37	gold quality
bone marrow	UBERON:0002371	96.35	gold quality
ileal mucosa	UBERON:0000331	96.21	gold quality
bone marrow cell	CL:0002092	96.01	gold quality
stromal cell of endometrium	CL:0002255	95.97	gold quality
rectum	UBERON:0001052	95.96	gold quality
ganglionic eminence	UBERON:0004023	95.94	gold quality
placenta	UBERON:0001987	95.85	gold quality
blood	UBERON:0000178	95.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.41	gold quality
right adrenal gland cortex	UBERON:0035827	95.02	gold quality
right adrenal gland	UBERON:0001233	94.98	gold quality
secondary oocyte	CL:0000655	94.87	gold quality
palpebral conjunctiva	UBERON:0001812	94.79	gold quality
bronchial epithelial cell	CL:0002328	94.72	gold quality
left adrenal gland	UBERON:0001234	94.72	gold quality
left adrenal gland cortex	UBERON:0035825	94.49	gold quality
adrenal cortex	UBERON:0001235	94.46	gold quality
pancreas	UBERON:0001264	94.42	gold quality
adrenal gland	UBERON:0002369	94.31	gold quality
saliva-secreting gland	UBERON:0001044	94.19	gold quality
body of pancreas	UBERON:0001150	94.15	gold quality
mucosa of transverse colon	UBERON:0004991	94.11	gold quality
nasal cavity epithelium	UBERON:0005384	94.07	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	51.64
E-MTAB-10042	yes	24.55
E-MTAB-9221	yes	15.48
E-MTAB-9388	yes	7.94
E-HCAD-9	yes	6.85
E-HCAD-1	yes	4.97
E-ENAD-17	no	3123.70
E-HCAD-10	no	3.14
E-MTAB-9467	no	1.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HBA1	Repression
HBB	Repression

Upstream regulators (CollecTRI, top): ELK1, EP300, HDAC1, MZF1, NFKB, SP1, STAT1

miRNA regulators (miRDB)

84 targeting EIF2AK1, 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-340-5P	100.00	72.50	4437
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-488-3P	99.61	68.79	1731

Literature-anchored findings (GeneRIF, showing 17)

• autophosphorylation of Thr485 is essential for the hyperphosphorylation and activation of HRI and is required for the acquisition of the eIF2alpha kinase activity (PMID:12767237)
• These data establish for the first time, the possible mechanisms of regulation of hHRI gene expression under normal physiological condition, hemin exposure and stress. (PMID:19133234)
• During lead-stress, the regulation of hHRI mRNA translation is mediated through its 5’-untranslated region (UTR) that interacts with specific trans-acting factors. (PMID:23357686)
• Dephosphorylation of eIF2alpha, specifically in the cortex, is both correlated with and necessary for normal memory consolidation. (PMID:23392680)
• Infection-associated functions of HRI (an eIF2alpha kinase) are independent of its activity as a regulator of protein synthesis. (PMID:23874749)
• data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons (PMID:27557499)
• structural and functional stability of HRI (PMID:27888007)
• The antiviral kinase PKR plays a critical role in controlling HCMV replication. (PMID:27974558)
• Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies. (PMID:30026227)
• Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex (PMID:30170366)
• Recently, HRI has been implicated in the regulation of human fetal hemoglobin production. Therefore, HRI-integrated stress response has emerged as a potential therapeutic target for hemoglobinopathies. especially under iron/heme deficiency and beta-thalassemia. [review] (PMID:31554636)
• mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway; the OMA1-DELE1-HRI pathway represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction (PMID:32132707)
• Human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. (PMID:32197074)
• The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. (PMID:32299090)
• The eIF2alpha kinase HRI in innate immunity, proteostasis, and mitochondrial stress. (PMID:32892501)
• The eIF2alpha kinase HRI triggers the autophagic clearance of cytosolic protein aggregates. (PMID:33168630)
• Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts. (PMID:35926182)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2ak1	ENSDARG00000093182
mus_musculus	Eif2ak1	ENSMUSG00000029613
rattus_norvegicus	Eif2ak1	ENSRNOG00000001050
drosophila_melanogaster	Wee1	FBGN0011737

Paralogs (8): EIF2AK2 (ENSG00000055332), STK35 (ENSG00000125834), PKMYT1 (ENSG00000127564), EIF2AK4 (ENSG00000128829), WEE1 (ENSG00000166483), EIF2AK3 (ENSG00000172071), PDIK1L (ENSG00000175087), WEE2 (ENSG00000214102)

Protein

Protein identifiers

Eukaryotic translation initiation factor 2-alpha kinase 1 — Q9BQI3 (reviewed: Q9BQI3)

Alternative names: Heme-controlled repressor, Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase, Heme-regulated inhibitor, Hemin-sensitive initiation factor 2-alpha kinase

All UniProt accessions (4): Q9BQI3, C9J7U7, F8WCM0, H7C033

UniProt curated annotations — full annotation on UniProt →

Function. Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions. Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming. Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. It thereby plays an essential protective role for RBC survival in anemias of iron deficiency. Iron deficiency also triggers activation by full-length DELE1. Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming. Also acts as an activator of mitophagy in response to mitochondrial damage: catalyzes phosphorylation of eIF-2-alpha (EIF2S1) following activation by S-DELE1, thereby promoting mitochondrial localization of EIF2S1, triggering PRKN-independent mitophagy.

Subunit / interactions. Synthesized in an inactive form that binds to the N-terminal domain of CDC37. Has to be associated with a multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation and activation by autophosphorylation. The phosphatase PPP5C modulates this activation. Homodimer; homodimerizes in presence of heme, forming a disulfide-linked inactive homodimer. Interacts with DELE1; binds both to full-length DELE1 and processed form of DELE1 (S-DELE1) in response to stress, leading to activate its protein kinase activity and trigger the integrated stress response (ISR).

Post-translational modifications. Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-488 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations. Ubiquitinated and degraded by the SIFI complex once the mitochondrial stress has been resolved, thereby providing stress response silencing. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1.

Disease relevance. Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (LEMSPAD) [MIM:618878] A disorder characterized by delayed motor development, speech delay with dysarthria, hypertonia, progressive spasticity, hyperreflexia, and bradykinesia. Cognition is normal. Patients manifest anxiety and attention deficit-hyperactivity disorder. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. In normal conditions, the protein kinase activity is inhibited; inhibition is relieved by various stress conditions. Inhibited by heme: in presence of heme, forms a disulfide-linked inactive homodimer. Heme depletion relieves inhibition and stimulates kinase activity by autophosphorylation. Inhibited by the heme metabolites biliverdin and bilirubin. Induced by oxidative stress generated by arsenite treatment. Binding of nitric oxide (NO) to the heme iron in the N-terminal heme-binding domain activates the kinase activity, while binding of carbon monoxide (CO) suppresses kinase activity. Protein kinase activity is also activated upon binding to DELE1 in response to various stress, triggering the integrated stress response (ISR): activated by full-length DELE1 in response to iron deficiency, while it is activated by the processed form of DELE1 (S-DELE1) in response to mitochondrial stress.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BQI3-1	1	yes
Q9BQI3-2	2

RefSeq proteins (2): NP_001127807, NP_055228* (*=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
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050339	CC_SR_Kinase	Family
IPR054521	HRI2_3H	Domain

Pfam: PF00069, PF22949

Catalyzed reactions (Rhea), 2 shown:

• 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 (34 total): sequence variant 10, sequence conflict 7, modified residue 4, binding site 2, repeat 2, region of interest 2, chain 1, domain 1, site 1, splice variant 1, short sequence motif 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQI3-F1	64.31	0.22

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 (2): 80 (heme-binding); 442 (proton acceptor)

Ligand- & substrate-binding residues (2): 196; 173–181

Post-translational modifications (4): 285, 486, 488, 493

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency
R-HSA-9840373	Cellular response to mitochondrial stress

MSigDB gene sets: 227 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_INFLAMMATORY_RESPONSE, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_TRANSLATIONAL_INITIATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, chr7p22, GOBP_MACROAUTOPHAGY, GNF2_ANK1, GOBP_NEGATIVE_REGULATION_OF_TRANSLATIONAL_INITIATION, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS

GO Biological Process (23): acute inflammatory response (GO:0002526), regulation of translational initiation (GO:0006446), phagocytosis (GO:0006909), negative regulation of cell population proliferation (GO:0008285), macrophage differentiation (GO:0030225), negative regulation of translational initiation by iron (GO:0045993), obsolete protoporphyrinogen IX metabolic process (GO:0046501), protein autophosphorylation (GO:0046777), negative regulation of hemoglobin biosynthetic process (GO:0046986), establishment of localization in cell (GO:0051649), multicellular organismal-level iron ion homeostasis (GO:0060586), protein localization to mitochondrion (GO:0070585), integrated stress response signaling (GO:0140467), HRI-mediated signaling (GO:0140468), positive regulation of mitophagy (GO:1901526), response to iron ion starvation (GO:1990641), mitophagy (GO:0000423), translational initiation (GO:0006413), regulation of translation (GO:0006417), protein phosphorylation (GO:0006468), response to stress (GO:0006950), negative regulation of translation (GO:0017148), regulation of hemoglobin biosynthetic process (GO:0046984)

GO Molecular Function (11): eukaryotic translation initiation factor 2alpha kinase activity (GO:0004694), ATP binding (GO:0005524), heme binding (GO:0020037), protein homodimerization activity (GO:0042803), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular responses to stress	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
protein kinase activity	2
cellular anatomical structure	2
inflammatory response	1
translational initiation	1
regulation of translation	1
endocytosis	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
regulation of translational initiation by iron	1
negative regulation of translational initiation	1
protein phosphorylation	1
negative regulation of macromolecule biosynthetic process	1
hemoglobin biosynthetic process	1
regulation of hemoglobin biosynthetic process	1
negative regulation of protein metabolic process	1
establishment of localization	1
cellular localization	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
multicellular organismal-level chemical homeostasis	1
protein localization to organelle	1
cellular response to stress	1
intracellular signaling cassette	1
integrated stress response signaling	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
response to metal ion starvation	1
autophagy of mitochondrion	1
macroautophagy	1
formation of translation initiation ternary complex	1
metabolic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
phosphorylation	1

Protein interactions and networks

STRING

1928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2AK1	EIF2S1	P05198	903
EIF2AK1	ANG	P03950	694
EIF2AK1	ATF4	P18848	655
EIF2AK1	RABIF	P47224	639
EIF2AK1	EIF2S2	P20042	586
EIF2AK1	EIF5	P55010	586
EIF2AK1	XBP1	P17861	574
EIF2AK1	EIF2S3	P41091	541
EIF2AK1	HSP90B1	P14625	539
EIF2AK1	EIF4A2	Q14240	533
EIF2AK1	EIF4A1	P04765	532
EIF2AK1	ATF6	P18850	530
EIF2AK1	ATF5	Q9Y2D1	499
EIF2AK1	EIF4G1	Q04637	491
EIF2AK1	EIF4E	P06730	483

IntAct

32 interactions, top by confidence:

A	B	Type	Score
CDC37	HSP90AB1	psi-mi:“MI:0914”(association)	0.930
FASLG	PRMT2	psi-mi:“MI:0914”(association)	0.640
HSPA8	EIF2AK1	psi-mi:“MI:0915”(physical association)	0.560
HSP90AB1	EIF2AK1	psi-mi:“MI:0915”(physical association)	0.560
CDK6	CCNT1	psi-mi:“MI:0914”(association)	0.530
CCDC127	CETN3	psi-mi:“MI:0914”(association)	0.530
EIF2AK1	H1-5	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK1	HSPB8	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK1	EIF2A	psi-mi:“MI:0915”(physical association)	0.400
DELE1	EIF2AK1	psi-mi:“MI:0915”(physical association)	0.400
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
HSPA8	PPP6C	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
EIF2AK1	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
CDC37	MAP2K7	psi-mi:“MI:0914”(association)	0.350
EIF2AK1	AP3B1	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	POLD1	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	ATRX	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	MFAP1	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	NAF1	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	EAF1	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	RBM14	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	DDX20	psi-mi:“MI:0915”(physical association)	0.000
DISC1	EIF2AK1	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	nhaA	psi-mi:“MI:0915”(physical association)	0.000
EIF2AK1	btuC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): EIF2AK1 (Affinity Capture-MS), EIF2AK1 (Affinity Capture-MS), EIF2AK1 (Affinity Capture-MS), EIF2AK1 (Affinity Capture-MS), EIF2AK1 (Affinity Capture-MS), EIF2AK1 (Affinity Capture-MS), EAF1 (Affinity Capture-MS), DDX20 (Affinity Capture-MS), NAF1 (Affinity Capture-MS), ATRX (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), POLD1 (Affinity Capture-MS), RBM14 (Affinity Capture-MS), MFAP1 (Affinity Capture-MS), EIF2AK1 (Affinity Capture-MS)

ESM2 similar proteins: A1E2V0, A5D8Q0, A9JTP3, A9ULZ2, B1B1A0, O08863, O62640, P33279, P36406, P36407, P42573, P51784, P98170, Q13049, Q13075, Q13489, Q13490, Q1L8G6, Q24307, Q4R8E0, Q5BKL8, Q60989, Q62210, Q63185, Q6P5D3, Q6ZPS6, Q6ZUJ8, Q7Z2W4, Q80Z32, Q8C7M3, Q8CH72, Q8JHV9, Q8K337, Q8N1W1, Q8R151, Q90660, Q95M71, Q95M72, Q96P09, Q9BQI3

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

7 interactions.

A	Effect	B	Mechanism
EIF2AK1	up-regulates	EIF2S1	phosphorylation
EIF2AK1	down-regulates	EIF2S1	phosphorylation
EIF2AK1	“down-regulates quantity by repression”	HBB	“transcriptional regulation”
EIF2AK1	“down-regulates quantity by repression”	HBA1	“transcriptional regulation”
EIF2AK1	“down-regulates activity”	EIF2S1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	5	16.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	164
Likely benign	71
Benign	18

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1723215	Single allele	Pathogenic
225106	NM_006303.4(AIMP2):c.575-2A>G	Pathogenic
872212	NM_006303.4(AIMP2):c.658_659del (p.Leu220fs)	Pathogenic

SpliceAI

3325 predictions. Top by Δscore:

Variant	Effect	Δscore
7:6024707:ACC:A	donor_gain	1.0000
7:6024708:CCC:C	donor_gain	1.0000
7:6026727:CATTT:C	donor_gain	1.0000
7:6026731:T:TA	donor_gain	1.0000
7:6026958:CTGA:C	acceptor_gain	1.0000
7:6026959:TGA:T	acceptor_gain	1.0000
7:6026962:C:CC	acceptor_gain	1.0000
7:6028916:A:AC	donor_gain	1.0000
7:6028917:C:CC	donor_gain	1.0000
7:6028917:CT:C	donor_gain	1.0000
7:6028917:CTCTT:C	donor_gain	1.0000
7:6028922:C:A	donor_gain	1.0000
7:6029011:C:CT	acceptor_gain	1.0000
7:6029028:CTTGG:C	acceptor_gain	1.0000
7:6029033:C:CC	acceptor_gain	1.0000
7:6032835:A:AG	acceptor_gain	1.0000
7:6032836:A:G	acceptor_gain	1.0000
7:6032837:A:G	acceptor_gain	1.0000
7:6032837:AGC:A	acceptor_loss	1.0000
7:6032838:G:GG	acceptor_gain	1.0000
7:6032838:GCC:G	acceptor_gain	1.0000
7:6032932:GTCAG:G	donor_gain	1.0000
7:6032937:G:GA	donor_loss	1.0000
7:6032938:T:G	donor_loss	1.0000
7:6037418:ACTT:A	donor_loss	1.0000
7:6037419:CTTA:C	donor_loss	1.0000
7:6037420:TTA:T	donor_loss	1.0000
7:6037421:TACC:T	donor_loss	1.0000
7:6037423:C:CT	donor_loss	1.0000
7:6037526:T:C	acceptor_gain	1.0000

AlphaMissense

4119 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:6044595:A:G	W233R	0.999
7:6044595:A:T	W233R	0.999
7:6046113:T:A	K196N	0.999
7:6046113:T:G	K196N	0.999
7:6046114:T:A	K196I	0.999
7:6047040:A:C	F167L	0.999
7:6047040:A:T	F167L	0.999
7:6047042:A:G	F167L	0.999
7:6026924:A:G	L523P	0.998
7:6026947:G:C	S515R	0.998
7:6026947:G:T	S515R	0.998
7:6026949:T:G	S515R	0.998
7:6028982:G:C	D461E	0.998
7:6028982:G:T	D461E	0.998
7:6028983:T:A	D461V	0.998
7:6028983:T:C	D461G	0.998
7:6028983:T:G	D461A	0.998
7:6037431:T:A	D442V	0.998
7:6037431:T:C	D442G	0.998
7:6037431:T:G	D442A	0.998
7:6037434:C:G	R441P	0.998
7:6038640:A:G	M384T	0.998
7:6044593:C:A	W233C	0.998
7:6044593:C:G	W233C	0.998
7:6044612:A:T	V227D	0.998
7:6046120:G:T	A194E	0.998
7:6026779:T:A	R571S	0.997
7:6026779:T:G	R571S	0.997
7:6026894:C:G	R533P	0.997
7:6026942:C:T	G517D	0.997

dbSNP variants (sampled 300 via entrez): RS1000074241 (7:6047059 G>A,C), RS1000337216 (7:6027693 A>T), RS1000339927 (7:6052555 A>G), RS1000480877 (7:6030727 G>C), RS1000547793 (7:6027020 C>A,T), RS1000634653 (7:6047153 C>A,T), RS1000692305 (7:6043492 G>A), RS1000795134 (7:6038370 G>A,C), RS1000966395 (7:6033220 C>A,T), RS1000982849 (7:6057578 C>T), RS1001075498 (7:6048013 C>T), RS1001190267 (7:6033331 A>C), RS1001223422 (7:6030472 G>A,C), RS1001275845 (7:6030671 G>A,C,T), RS1001289287 (7:6057222 TC>T)

Disease associations

OMIM: gene MIM:613635 | disease phenotypes: MIM:618878, MIM:120435, MIM:618006

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome	Limited	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (4): leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (MONDO:0030036), Lynch syndrome 1 (MONDO:0007356), leukodystrophy, hypomyelinating, 17 (MONDO:0054817), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Lynch syndrome (Orphanet:144)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0002061	Lower limb spasticity
HP:0002067	Bradykinesia
HP:0003593	Infantile onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0025352	Typically de novo
HP:0031936	Delayed ability to walk

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004611_71	High light scatter reticulocyte count	4.000000e-19
GCST004612_30	High light scatter reticulocyte percentage of red cells	4.000000e-19
GCST004619_181	Reticulocyte fraction of red cells	2.000000e-24
GCST004622_1	Reticulocyte count	6.000000e-24
GCST90002385_179	High light scatter reticulocyte count	1.000000e-57
GCST90002386_441	High light scatter reticulocyte percentage of red cells	5.000000e-60
GCST90002390_238	Mean corpuscular hemoglobin	4.000000e-15
GCST90002392_712	Mean corpuscular volume	8.000000e-13
GCST90002405_219	Reticulocyte count	8.000000e-51
GCST90002406_238	Reticulocyte fraction of red cells	1.000000e-55

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6029 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 97,668 (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
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL253969	OSI-632	2	1,150
CHEMBL3039525	GOLVATINIB	2	535
CHEMBL3182621	AZD-8330	1	2,794
CHEMBL3545083	RGB-286638	1	551
CHEMBL3545085	XL-228	1	936

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 27 [PMID: 19854648]	Inhibition	8.2	pIC50
RIPK1 inhibitor 22b	Inhibition	7.59	pIC50

ChEMBL bioactivities

57 potent at pChembl≥5 of 61 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	IC50	6.31	nM	CHEMBL573760
8.10	IC50	7.943	nM	CHEMBL578426
7.70	IC50	19.95	nM	CHEMBL576168
7.58	IC50	26	nM	CHEMBL4281823
7.50	IC50	31.62	nM	CHEMBL574005
7.43	IC50	37	nM	CHEMBL2441342
7.30	IC50	50.12	nM	CHEMBL578836
7.24	Kd	58	nM	ALVOCIDIB
7.21	IC50	61	nM	CHEMBL2441346
7.20	IC50	63.1	nM	CHEMBL574443
7.20	IC50	63.1	nM	CHEMBL565272
7.10	IC50	79.43	nM	CHEMBL583635
6.90	IC50	125.9	nM	CHEMBL574209
6.77	Kd	170	nM	AZD-4547
6.70	IC50	199.5	nM	CHEMBL573763
6.67	IC50	214	nM	CHEMBL2171122
6.60	IC50	251.2	nM	CHEMBL573770
6.60	IC50	251.2	nM	CHEMBL574009
6.50	IC50	316.2	nM	CHEMBL576948
6.47	Kd	335	nM	BARICITINIB
6.38	IC50	420	nM	CHEMBL2171124
6.34	IC50	460	nM	CHEMBL2441340
6.30	IC50	501.2	nM	CHEMBL575913
6.30	IC50	501.2	nM	CHEMBL582642
6.20	IC50	631	nM	CHEMBL574208
6.20	Kd	630	nM	BOSUTINIB
6.18	Kd	666	nM	REBASTINIB
6.10	IC50	794.3	nM	CHEMBL575914
6.10	IC50	794.3	nM	CHEMBL573280
6.06	Kd	870	nM	ALVOCIDIB
6.02	Kd	949	nM	DABRAFENIB
6.01	Kd	980	nM	FORETINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
6.00	IC50	1000	nM	CHEMBL575078
6.00	IC50	1000	nM	CHEMBL574006
6.00	Kd	1000	nM	FEDRATINIB
5.97	Kd	1080	nM	GOLVATINIB
5.90	IC50	1259	nM	CHEMBL575915
5.82	Kd	1500	nM	DEFOSBARASERTIB
5.80	IC50	1585	nM	CHEMBL583189
5.78	Kd	1661	nM	SILMITASERTIB
5.74	Kd	1821	nM	AZD-8330
5.73	IC50	1863	nM	CHEMBL2171132
5.69	Kd	2047	nM	MIDOSTAURIN
5.60	IC50	2512	nM	CHEMBL574010
5.60	IC50	2512	nM	CHEMBL578663
5.51	Kd	3100	nM	CEDIRANIB
5.50	IC50	3162	nM	CHEMBL577153

PubChem BioAssay actives

54 with measured affinity, of 589 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
3-[(2,6-dichlorophenyl)methylamino]-6,7-dimethoxy-1H-indeno[2,1-d]pyrazol-4-one	438225: Inhibition of human HRI kinase	ic50	0.0063	uM
N-[(2,6-dimethylphenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.0079	uM
N-[(2-chloro-6-methylphenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.0199	uM
1-[5-(4-amino-7-ethylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethoxy)phenyl]ethanone	1415186: Inhibition of recombinant human HRI (140 to end residues) using RSRSRSRSRSRSR as substrate after 120 mins in presence of [gamma-33P]-ATP by scintillation counting analysis	ic50	0.0260	uM
3-[[3-[(2,6-dichlorophenyl)methylamino]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-6-yl]oxy]propane-1,2-diol	438225: Inhibition of human HRI kinase	ic50	0.0316	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	777371: Inhibition of HRI (unknown origin) assessed as EIF2AK1 phosphorylation	ic50	0.0370	uM
N-[(2-chloro-6-methylphenyl)methyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.0501	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0580	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	777371: Inhibition of HRI (unknown origin) assessed as EIF2AK1 phosphorylation	ic50	0.0610	uM
6,7-dimethoxy-N-[(2-methylphenyl)methyl]-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.0631	uM
N-[(2,6-dichlorophenyl)methyl]-6,7-dimethoxy-1H-[1]benzofuro[3,2-c]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.0631	uM
N-[(2,6-dichlorophenyl)methyl]-6,7-dimethoxy-4,4-dioxo-1H-[1]benzothiolo[3,2-c]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.0794	uM
N-[(2-chloro-6-methylphenyl)methyl]-5,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.1259	uM
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1700	uM
N-[(2-chlorophenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.1995	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-chlorophenyl)ethanone	702104: Inhibition of HRI assessed as EIF2AK1 phosphorylation	ic50	0.2140	uM
3-N-[(2-chloro-6-methylphenyl)methyl]-7-N,7-N-dimethyl-1,4-dihydroindeno[2,1-d]pyrazole-3,7-diamine	438225: Inhibition of human HRI kinase	ic50	0.2512	uM
N-[(2-chloro-6-methylphenyl)methyl]-4,6-dioxa-11,12-diazatetracyclo[7.6.0.03,7.010,14]pentadeca-1,3(7),8,10(14),12-pentaen-13-amine	438225: Inhibition of human HRI kinase	ic50	0.2512	uM
N-[(2-chloro-6-methylphenyl)methyl]-7-ethyl-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.3162	uM
Baricitinib	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.3350	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone	702104: Inhibition of HRI assessed as EIF2AK1 phosphorylation	ic50	0.4200	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	777371: Inhibition of HRI (unknown origin) assessed as EIF2AK1 phosphorylation	ic50	0.4600	uM
N-[(2-chloro-6-methylphenyl)methyl]-6-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.5012	uM
N-[(2-chloro-6-methylphenyl)methyl]-6,7-dimethoxy-1H-[1]benzothiolo[3,2-c]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.5012	uM
Bosutinib	625080: Binding constant for EIF2AK1 kinase domain	kd	0.6300	uM
N-benzyl-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.6310	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.6660	uM
7-bromo-N-[(2-chloro-6-methylphenyl)methyl]-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.7943	uM
N-[(2-chloro-6-methylphenyl)methyl]-5-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	0.7943	uM
Dabrafenib	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.9490	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625080: Binding constant for EIF2AK1 kinase domain	kd	0.9800	uM
Fedratinib	625080: Binding constant for EIF2AK1 kinase domain	kd	1.0000	uM
N-[(2-chloro-6-methylphenyl)methyl]-7-methylsulfanyl-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	1.0000	uM
N-[(3-chlorophenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	1.0000	uM
1-N’-[2-fluoro-4-[[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]-4-pyridinyl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0800	uM
N-[(2,4-dichlorophenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	1.2589	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	625080: Binding constant for EIF2AK1 kinase domain	kd	1.5000	uM
N-[(2-chloro-6-methylphenyl)methyl]-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	1.5849	uM
5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.6610	uM
2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.8210	uM
1-[5-[4-amino-7-(1-methylpyrazol-4-yl)thieno[3,2-c]pyridin-3-yl]-2,3-dihydroindol-1-yl]-2-phenylethanone	702104: Inhibition of HRI assessed as EIF2AK1 phosphorylation	ic50	1.8630	uM
Midostaurin	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.0470	uM
N-[(2,6-dichlorophenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	2.5119	uM
N-[(4-chlorophenyl)methyl]-6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	2.5119	uM
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline	625080: Binding constant for EIF2AK1 kinase domain	kd	3.1000	uM
6,7-dimethoxy-N-[(2-methoxyphenyl)methyl]-1,4-dihydroindeno[2,1-d]pyrazol-3-amine	438225: Inhibition of human HRI kinase	ic50	3.1623	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.3420	uM
3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.5720	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide;hydrochloride	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.7240	uM
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[2,1-d]pyrazol-5-yl]-3-morpholin-4-ylurea	1424984: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.8030	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases reaction, affects reaction, increases phosphorylation	2
Valproic Acid	affects expression, increases expression	2
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
beta-lapachone	decreases expression	1
sodium arsenite	affects binding, increases reaction	1
coumarin	increases phosphorylation	1
perfluorooctane sulfonic acid	increases expression	1
abrine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Diclofenac	affects expression	1
Doxorubicin	decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Dronabinol	increases expression	1
Thiram	decreases expression	1
Josamycin	affects response to substance	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

124 unique, capped per target: 124 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1038414	Binding	Residual activity of HRI at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1NQ	HAP1 EIF2AK1 (-) EIF2AK3 (-) 1	Cancer cell line	Male
CVCL_E1NR	HAP1 EIF2AK1 (-) EIF2AK3 (-) 2	Cancer cell line	Male
CVCL_E1NS	HAP1 EIF2AK1 (-) EIF2AK4 (-) 1	Cancer cell line	Male
CVCL_E1NT	HAP1 EIF2AK1 (-) EIF2AK4 (-) 2	Cancer cell line	Male
CVCL_E1NU	HAP1 EIF2AK1 (-) EIF2AK4 (-) 3	Cancer cell line	Male
CVCL_SL63	HAP1 EIF2AK1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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