EIF2AK4

Summary

EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4, HGNC:19687) is a protein-coding gene on chromosome 15q15.1, encoding eIF-2-alpha kinase GCN2 (Q9P2K8). Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability. It is a selective cancer dependency (DepMap: 10.1% of cell lines).

This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2.

Source: NCBI Gene 440275 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 588 total — 52 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 10.1% of screened cell lines
• MANE Select transcript: NM_001013703

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19687
Approved symbol	EIF2AK4
Name	eukaryotic translation initiation factor 2 alpha kinase 4
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	GCN2, KIAA1338
Ensembl gene	ENSG00000128829
Ensembl biotype	protein_coding
OMIM	609280
Entrez	440275

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 16 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 TEC

ENST00000263791, ENST00000558557, ENST00000558629, ENST00000558743, ENST00000558823, ENST00000559032, ENST00000559311, ENST00000559624, ENST00000560648, ENST00000560855, ENST00000624709, ENST00000917945, ENST00000917946, ENST00000917947, ENST00000917948, ENST00000917949, ENST00000917950, ENST00000917951, ENST00000917952, ENST00000917953, ENST00000958415, ENST00000958416

RefSeq mRNA: 1 — MANE Select: NM_001013703 NM_001013703

CCDS: CCDS42016

Canonical transcript exons

ENST00000263791 — 39 exons

Exon	Start	End
ENSE00000675147	39973592	39973749
ENSE00000675148	39976414	39976844
ENSE00000883788	39967344	39967879
ENSE00000883791	39978078	39978147
ENSE00000930960	39955620	39955768
ENSE00000942430	39961784	39961899
ENSE00000942431	39965686	39965843
ENSE00000942432	39972908	39973014
ENSE00000942433	39985805	39985888
ENSE00000942434	39987983	39988105
ENSE00000942435	39990273	39990377
ENSE00000942436	39992175	39992229
ENSE00000942437	39992769	39992848
ENSE00001156372	39953904	39953984
ENSE00001493153	39949116	39949268
ENSE00001493154	39943383	39943485
ENSE00001493155	39939505	39939617
ENSE00002543296	39934115	39934339
ENSE00003458923	40025977	40026089
ENSE00003459476	40002713	40002788
ENSE00003471936	40008027	40008195
ENSE00003487360	40011281	40011346
ENSE00003496737	40007016	40007065
ENSE00003503609	40009614	40009730
ENSE00003535812	40030359	40030456
ENSE00003545623	40000988	40001224
ENSE00003569227	40032169	40032237
ENSE00003569259	40003193	40003314
ENSE00003593831	39996964	39997065
ENSE00003596178	40017108	40017242
ENSE00003611678	40029406	40029464
ENSE00003622105	40016502	40016672
ENSE00003629554	40022519	40022605
ENSE00003647571	40034326	40034444
ENSE00003666925	40035027	40035591
ENSE00003675551	40020899	40021027
ENSE00003687920	40019093	40019200
ENSE00003690765	39998731	39998784
ENSE00003693480	40032757	40032801

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 93.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.4064 / max 308.3397, expressed in 1802 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146057	28.0539	1802
146056	0.2492	90
146061	0.0275	8
146060	0.0221	7
146063	0.0171	7
146062	0.0156	6
146059	0.0122	4
146058	0.0088	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	93.20	gold quality
pituitary gland	UBERON:0000007	92.33	gold quality
bone marrow cell	CL:0002092	92.02	gold quality
stromal cell of endometrium	CL:0002255	91.27	gold quality
layer of synovial tissue	UBERON:0007616	90.57	gold quality
tibia	UBERON:0000979	90.45	gold quality
calcaneal tendon	UBERON:0003701	89.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.77	gold quality
nucleus accumbens	UBERON:0001882	89.73	gold quality
left uterine tube	UBERON:0001303	89.60	gold quality
caudate nucleus	UBERON:0001873	89.55	gold quality
hypothalamus	UBERON:0001898	89.41	gold quality
synovial joint	UBERON:0002217	89.40	gold quality
anterior cingulate cortex	UBERON:0009835	89.33	gold quality
omental fat pad	UBERON:0010414	89.24	gold quality
peritoneum	UBERON:0002358	89.23	gold quality
putamen	UBERON:0001874	89.14	gold quality
nerve	UBERON:0001021	89.05	gold quality
tibial nerve	UBERON:0001323	89.05	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.03	gold quality
right lobe of liver	UBERON:0001114	88.96	gold quality
smooth muscle tissue	UBERON:0001135	88.94	gold quality
right lobe of thyroid gland	UBERON:0001119	88.91	gold quality
amygdala	UBERON:0001876	88.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.85	gold quality
left coronary artery	UBERON:0001626	88.84	gold quality
right coronary artery	UBERON:0001625	88.69	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.69	gold quality
left lobe of thyroid gland	UBERON:0001120	88.59	gold quality
right lung	UBERON:0002167	88.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	23.86
E-CURD-122	yes	12.51

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
ATF3	Activation
DDIT3	Activation

Upstream regulators (CollecTRI, top): SPI1

miRNA regulators (miRDB)

26 targeting EIF2AK4, 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-3120-5P	100.00	65.56	965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-4733-5P	97.75	67.44	866
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-431-5P	96.16	66.50	652

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• MEK functions to enhance GCN2-dependent eIF2alpha phosphorylation rather than suppressing dephosphorylation (PMID:18287093)
• UV-induced eIF2alpha phosphorylation by activation of both PERK and GCN2 via oxidative stress and l-arginine starvation signaling pathways. (PMID:19586904)
• Data show that impairment of autophagy stimulates PS1 expression and gamma-secretase activity through GCN2. (PMID:20168091)
• The authors conclude that the GCN2-eIF2alpha-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches. (PMID:20473272)
• GCN2 and its downstream target, the transcriptional activator ATF4, is critical for proliferation and survival of tumour cells after starvation for amino acids or glucose and is essential for growth in vivo in a xenograft model. (PMID:20551969)
• The results suggest that GCN2 pathways can mediate the limiting effects of Gln deprivation on protein synthesis according to its severity. (PMID:21113813)
• the GCN2/eIF2alpha/ATF4 pathway is essential for the induction of the TRB3 gene transcription (PMID:21203563)
• Changes in translational control of mitochondrial proteins are signaled by the activation of AMPK (AMP-activated protein kinase) and GCN2, leading also to the activation of autophagy. (PMID:22435535)
• The activation of autophagy in response to interferon (IFN)-gamma is promoted by tryptophan depletion and relies, at least in part, on the activation of GCN2-eIF2alpha kinase in kidney epithelial cells. (PMID:22896630)
• GCN2 leading to inhibition of viral RNA translation, and that HIV-1 protease cleaves GCN2 to overcome its antiviral effect. (PMID:23110064)
• In this review, GCN2 senses the absence of one or more amino acids by virtue of direct binding to cognate tRNAs. (PMID:23216249)
• GCN2 has a role as an early mediator in the cellular response to HIV-1 infection (PMID:23417324)
• Data indicate that suppressing GCN2 and activating transcription factor 4 (ATF4), expression decreased Amino acid deprivation (AAD)-induced VEGF expression. (PMID:23908598)
• Mutations in EIF2AK4 are likely to cause autosomal-recessive pulmonary capillary hemangiomatosis in familial and some nonfamilial cases. (PMID:24135949)
• REVIEW: roles of GCN2 (PMID:24256275)
• EIF2AK4 mutations cause pulmonary veno-occlusive disease. (PMID:24292273)
• Association of EIF2AKE with body mass index in Chinese has been confirmed and is suggested to be ’ethnic specific’. (PMID:24827717)
• This study is the first to examine the perceptual response to CPET in patients with PVOD who were carriers of EIF2AK4 mutations compared with PAH patients matched for resting haemodynamics and pulmonary function (PMID:25142489)
• p58IPK is a general inhibitor of the eIF2alpha kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2alpha phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis (PMID:25329545)
• Data show that sequenced eukaryotic translation initiation factor 2 alpha kinase 4 protein (EIF2AK4) with a homozygous mutation in all five families: c.3344C>T(p.P1115L). (PMID:25512148)
• GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. (PMID:25589675)
• GCN2 activation and phosphorylation of eIF2alpha in response to mTORC1 inhibition are necessary for autophagy. (PMID:25759478)
• Targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis in melanoma. (PMID:26082174)
• IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages. (PMID:26147366)
• EIF2AK4 mutation was associated with pulmonary veno-occlusive disease. PVOD patients who were not significantly exposed to trichloroethylene were more likely to harbour EIF2AK4 mutations. (PMID:26541523)
• Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization (PMID:26543160)
• IDO, through GCN2 kinase activation, downregulates the levels of TCRcomplex tchain and cMyc, resulting in the suppression of Tcell proliferation and a reduction in the levels of LDHA and GLS2 (PMID:26647830)
• This is the first reported case of EIF2AK4 mutation in PVOD in a Chinese patient population. We found the frameshift EIF2AK4 mutation c.1392delT (p.Arg465fs) in this case. (PMID:27684876)
• EIF2AK4 mutations can also contribute to autosomal dominantly inherited pulmonary arterial hypertension. (PMID:27809840)
• A novel homozygous EIF2AK4 mutation (c.257+4A>C) was identified in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+4A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 patients with IPAH had biallelic EIF2AK4 mutations. (PMID:27884767)
• in response to vemurafenib, BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 (GCN2), an eIF2alpha kinase sensing amino acid levels (PMID:27965097)
• A novel homozygous EIF2AK4 mutation (c.257+4A>C) was identified in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+4A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 patients with IPAH had biallelic EIF2AK4 mutations. (PMID:28012804)
• Heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis is rare. (PMID:28087362)
• Data show that siRNA-mediated depletion of general control nonderepressible 2 (GCN2) increases small RNA transcripts such as tRNA and 5S rRNA, and induces the p53 pathway activation. (PMID:28189689)
• Data show that eukaryotic translation initiation factor 2 alpha kinase 4 protein (GCN2) interacts with HIV-1 integrase and is activated during HIV-1 infection. (PMID:28536474)
• Heritable Pulmonary Veno-occlusive Disease and/or Pulmonary Capillary Hemangiomatosis is an autosomal recessive disease because of biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene. (PMID:28661905)
• The biallelic founder mutation in EIF2AK4 was found in all affected cases and 2 unaffected relatives. Family screening showed 34.2% of healthy heterozygotes, high consanguinity, young age at childbirth, and frequent multiparity. Prognosis was bleak, with significant differences depending on tolerance to PVD. (PMID:28697925)
• Present study shows that the GCN2-dependent integrated stress response may have a pathophysiological effect on human renal tubular cells. (PMID:28894140)
• Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable pulmonary arterial hypertension. (PMID:28972005)
• Heritable pulmonary arterial hypertension is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. Biallelic germline mutations in the gene EIF2AK4 are now associated with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. [review] (PMID:29032562)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000104276
mus_musculus	Eif2ak4	ENSMUSG00000005102
rattus_norvegicus	Eif2ak4	ENSRNOG00000006027
drosophila_melanogaster	Gcn2	FBGN0019990

Paralogs (8): EIF2AK2 (ENSG00000055332), EIF2AK1 (ENSG00000086232), STK35 (ENSG00000125834), PKMYT1 (ENSG00000127564), WEE1 (ENSG00000166483), EIF2AK3 (ENSG00000172071), PDIK1L (ENSG00000175087), WEE2 (ENSG00000214102)

Protein

Protein identifiers

eIF-2-alpha kinase GCN2 — Q9P2K8 (reviewed: Q9P2K8)

Alternative names: Eukaryotic translation initiation factor 2-alpha kinase 4, GCN2-like protein

All UniProt accessions (4): Q9P2K8, H0YME5, H0YND8, H0YNY9

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 low amino acid availability. Plays a role as an activator of the integrated stress response (ISR) required for adaptation to amino acid starvation. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs. Required for the translational induction of protein kinase PRKCH following amino acid starvation. Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation. Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways. Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication. (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation.

Subunit / interactions. Homodimer; homodimerization is important for kinase activation by uncharged tRNAs. Interacts with GCN1; this interaction stimulates EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety of stress conditions, such as amino acid depletion, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation. Interacts with DNAJC3; this interaction inhibits EIF2AK4/GCN2 kinase activity during endoplasmic reticulum (ER), hypothermic and amino acid-starving stress conditions. Interacts with MAP3K20; activates EIF2AK4/GCN2 kinase activity in response to moderate ribotoxic stress. (Microbial infection) Interacts with hepatitis E virus (HEV) ORF1 protease; this interaction inhibits dimerization of EIF2AK4 and prevents EIF2AK4-mediated phosphorylation of EIF2A.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Expressed in lung, smooth muscle cells and macrophages.

Post-translational modifications. Autophosphorylated; autophosphorylation on Thr-899 is increased upon amino acid starvation and in UV irradiation cells and inhibited in presence of IMPACT.

Disease relevance. Pulmonary venoocclusive disease 2, autosomal recessive (PVOD2) [MIM:234810] A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The histidyl-tRNA synthetase-like region and protein kinase domains are necessary for eIF-2-alpha kinase activity and eIF-2-alpha-mediated translational control. The histidyl-tRNA synthetase-like domain is necessary for binding to uncharged tRNAs. Kinase domain 1 is a degenerate kinase domain.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9P2K8-1	1	yes
Q9P2K8-2	2
Q9P2K8-3	3

RefSeq proteins (1): NP_001013725* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR006575	RWD_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR016255	Gcn2	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR024435	HisRS-related_dom	Domain
IPR036621	Anticodon-bd_dom_sf	Homologous_superfamily
IPR041715	HisRS-like_core	Domain
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily
IPR050339	CC_SR_Kinase	Family

Pfam: PF00069, PF05773, PF12745, PF13393

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 (125 total): helix 37, strand 35, turn 11, sequence variant 11, modified residue 6, region of interest 6, compositionally biased region 4, sequence conflict 4, domain 3, splice variant 3, binding site 2, chain 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7E2K	X-RAY DIFFRACTION	2.04
7QWK	X-RAY DIFFRACTION	2.3
7E2M	X-RAY DIFFRACTION	2.35
6N3O	X-RAY DIFFRACTION	2.4
6N3L	X-RAY DIFFRACTION	2.61
7QQ6	X-RAY DIFFRACTION	2.8
6N3N	X-RAY DIFFRACTION	3.01
8T7T	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2K8-F1	73.75	0.23

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): 848 (proton acceptor)

Ligand- & substrate-binding residues (2): 596–604; 619

Post-translational modifications (6): 230, 667, 871, 899, 904, 1259

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency

MSigDB gene sets: 315 (showing top): GOBP_MEMORY, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_COGNITION, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, GOBP_BEHAVIOR, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_RESPONSE_TO_COLD, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH

GO Biological Process (34): DNA damage checkpoint signaling (GO:0000077), positive regulation of defense response to virus by host (GO:0002230), adaptive immune response (GO:0002250), T cell activation involved in immune response (GO:0002286), positive regulation of adaptive immune response (GO:0002821), regulation of translational initiation (GO:0006446), protein phosphorylation (GO:0006468), learning (GO:0007612), long-term memory (GO:0007616), regulation of translational initiation by eIF2 alpha phosphorylation (GO:0010998), viral translation (GO:0019081), negative regulation of translational initiation in response to stress (GO:0032057), obsolete negative regulation of CREB transcription factor activity (GO:0032792), cellular response to amino acid starvation (GO:0034198), cellular response to UV (GO:0034644), host-mediated suppression of viral genome replication (GO:0044828), negative regulation of neuron differentiation (GO:0045665), negative regulation of translational initiation (GO:0045947), protein autophosphorylation (GO:0046777), defense response to virus (GO:0051607), regulation of feeding behavior (GO:0060259), cellular response to cold (GO:0070417), positive regulation of translational initiation in response to starvation (GO:0071264), GCN2-mediated signaling (GO:0140469), positive regulation of long-term synaptic potentiation (GO:1900273), neuron projection extension (GO:1990138), response to amino acid starvation (GO:1990928), immune system process (GO:0002376), translational initiation (GO:0006413), regulation of translation (GO:0006417), signal transduction (GO:0007165), nervous system development (GO:0007399), response to endoplasmic reticulum stress (GO:0034976), regulation of cell cycle (GO:0051726)

GO Molecular Function (12): tRNA binding (GO:0000049), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), eukaryotic translation initiation factor 2alpha kinase activity (GO:0004694), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), RNA binding (GO:0003723), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), ubiquitin protein ligase activity (GO:0061630)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytosolic ribosome (GO:0022626)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	3
immune response	2
protein phosphorylation	2
protein kinase activity	2
cellular anatomical structure	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
regulation of defense response to virus by host	1
lymphocyte activation involved in immune response	1
T cell activation	1
adaptive immune response	1
regulation of adaptive immune response	1
positive regulation of immune response	1
regulation of translation	1
phosphorylation	1
protein modification process	1
learning or memory	1
memory	1
regulation of translational initiation in response to stress	1
viral process	1
viral gene expression	1
response to stress	1
negative regulation of translational initiation	1
cellular response to starvation	1
response to amino acid starvation	1
response to UV	1
cellular response to light stimulus	1
viral genome replication	1
host-mediated perturbation of viral process	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
regulation of translational initiation	1
negative regulation of translation	1
defense response	1
response to virus	1
RNA binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1

Protein interactions and networks

STRING

3020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2AK4	GCN1	Q92616	988
EIF2AK4	EIF2S1	P05198	974
EIF2AK4	EIF2B5	Q13144	849
EIF2AK4	ATF4	P18848	842
EIF2AK4	PPP6C	O00743	798
EIF2AK4	RABIF	P47224	785
EIF2AK4	MTOR	P42345	735
EIF2AK4	EPRS1	P07814	725
EIF2AK4	XBP1	P17861	712
EIF2AK4	EIF5	P55010	710
EIF2AK4	HSPA5	P11021	707
EIF2AK4	EIF4E	P06730	699
EIF2AK4	ASNS	P08184	697
EIF2AK4	LARS1	Q9P2J5	687
EIF2AK4	EIF4A2	Q14240	684

IntAct

69 interactions, top by confidence:

A	B	Type	Score
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
PSMC3	PSMD12	psi-mi:“MI:0914”(association)	0.640
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
TKT	POTEF	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
HSPA12B	EEF2K	psi-mi:“MI:0914”(association)	0.530
EIF2AK4	ITGB1	psi-mi:“MI:0915”(physical association)	0.400
EIF2A	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK4	PGM2L1	psi-mi:“MI:0915”(physical association)	0.400
MLF1	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
MLF2	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK4		psi-mi:“MI:0915”(physical association)	0.400
EIF2AK4	BAG2	psi-mi:“MI:0915”(physical association)	0.400
NUDCD3	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK4	PSMD2	psi-mi:“MI:0915”(physical association)	0.400
STIP1	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK4	CDC37	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK4	CACYBP	psi-mi:“MI:0915”(physical association)	0.400
AARSD1	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.400
EWSR1	EIF2AK4	psi-mi:“MI:0915”(physical association)	0.370
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350

BioGRID (104): EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Co-fractionation), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS), EIF2AK4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PRR9, A4IHD2, A4PBL4, B4F769, D4ACP5, F4HQE2, I3XHK1, O09053, O12944, O75417, O94762, P0DOY1, P56960, P70270, Q08D35, Q0PCS3, Q1LWH4, Q2VPA6, Q3B7N1, Q3UWM4, Q5NC05, Q5QJC2, Q5RDL2, Q5RHD1, Q5SXJ3, Q5ZJF6, Q6NU40, Q6NZP1, Q6NZQ2, Q6PFE3, Q6ZMT4, Q80Y44, Q8BGE5, Q8CGS6, Q8GT06, Q8IYD8, Q8TDG4, Q8VID5, Q92698, Q99NG0

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

4 interactions.

A	Effect	B	Mechanism
EIF2AK4	down-regulates	MARS1	phosphorylation
EIF2AK4	“down-regulates activity”	EIF2S1	phosphorylation
DNAJC3	“down-regulates activity”	EIF2AK4	binding
EIF2AK4	“down-regulates activity”	EIF2A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	5	15.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	23
Uncertain significance	180
Likely benign	115
Benign	149

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101527	NM_001013703.4(EIF2AK4):c.1153dup (p.Val385fs)	Pathogenic
101528	NM_001013703.4(EIF2AK4):c.3766C>T (p.Arg1256Ter)	Pathogenic
101529	NM_001013703.4(EIF2AK4):c.3448C>T (p.Arg1150Ter)	Pathogenic
101530	NM_001013703.4(EIF2AK4):c.860-1G>A	Pathogenic
1431295	NM_001013703.4(EIF2AK4):c.4669C>T (p.Arg1557Ter)	Pathogenic
1455657	NM_001013703.4(EIF2AK4):c.2431C>T (p.Arg811Ter)	Pathogenic
1706626	NM_001013703.4(EIF2AK4):c.301G>T (p.Glu101Ter)	Pathogenic
1706636	NM_001013703.4(EIF2AK4):c.1243del (p.Tyr415fs)	Pathogenic
1923326	NM_001013703.4(EIF2AK4):c.457_458del (p.Arg153fs)	Pathogenic
1947240	NM_001013703.4(EIF2AK4):c.1758C>A (p.Tyr586Ter)	Pathogenic
1971700	NM_001013703.4(EIF2AK4):c.2061_2076dup (p.Leu693fs)	Pathogenic
1977811	NM_001013703.4(EIF2AK4):c.4766C>A (p.Ser1589Ter)	Pathogenic
1983474	NM_001013703.4(EIF2AK4):c.4567_4570del (p.Phe1523fs)	Pathogenic
2091689	NM_001013703.4(EIF2AK4):c.3228_3229del (p.Arg1077fs)	Pathogenic
2091690	NM_001013703.4(EIF2AK4):c.4258del (p.Trp1420fs)	Pathogenic
2107943	NM_001013703.4(EIF2AK4):c.434_435del (p.Phe145fs)	Pathogenic
2662544	NM_001013703.4(EIF2AK4):c.3633dup (p.His1212fs)	Pathogenic
280131	NM_001013703.4(EIF2AK4):c.560_564del (p.Lys187fs)	Pathogenic
3042139	NM_001013703.4(EIF2AK4):c.1061del (p.Ser354fs)	Pathogenic
3622587	NM_001013703.4(EIF2AK4):c.249T>A (p.Tyr83Ter)	Pathogenic
3697511	NM_001013703.4(EIF2AK4):c.1021C>T (p.Gln341Ter)	Pathogenic
3698558	NM_001013703.4(EIF2AK4):c.4585del (p.Thr1529fs)	Pathogenic
3728967	NM_001013703.4(EIF2AK4):c.2863A>T (p.Arg955Ter)	Pathogenic
426050	NM_001013703.4(EIF2AK4):c.354_355del (p.Cys118fs)	Pathogenic
426051	NM_001013703.4(EIF2AK4):c.745C>T (p.Arg249Ter)	Pathogenic
426052	NM_001013703.4(EIF2AK4):c.1554-4C>A	Pathogenic
426053	NM_001013703.4(EIF2AK4):c.1928T>G (p.Leu643Arg)	Pathogenic
426054	NM_001013703.4(EIF2AK4):c.2136_2139dup (p.Ser714fs)	Pathogenic
426055	NM_001013703.4(EIF2AK4):c.2319+1G>A	Pathogenic
426056	NM_001013703.4(EIF2AK4):c.2458C>T (p.Arg820Ter)	Pathogenic

SpliceAI

6273 predictions. Top by Δscore:

Variant	Effect	Δscore
15:39934335:GACCG:G	donor_gain	1.0000
15:39934337:CCGGT:C	donor_loss	1.0000
15:39934338:CGGT:C	donor_loss	1.0000
15:39934339:GGT:G	donor_loss	1.0000
15:39934340:G:GG	donor_gain	1.0000
15:39934340:GTA:G	donor_loss	1.0000
15:39939613:GATGT:G	donor_gain	1.0000
15:39939616:GT:G	donor_gain	1.0000
15:39939618:G:GG	donor_gain	1.0000
15:39943382:GA:G	acceptor_gain	1.0000
15:39949107:C:G	acceptor_gain	1.0000
15:39949108:A:AG	acceptor_gain	1.0000
15:39949109:T:G	acceptor_gain	1.0000
15:39949111:TTTAG:T	acceptor_loss	1.0000
15:39949112:TTAGG:T	acceptor_loss	1.0000
15:39949113:TA:T	acceptor_loss	1.0000
15:39949115:G:GT	acceptor_loss	1.0000
15:39949264:AGGAG:A	donor_loss	1.0000
15:39949265:GGAG:G	donor_gain	1.0000
15:39949266:G:GT	donor_gain	1.0000
15:39949267:AGGT:A	donor_loss	1.0000
15:39949268:GGTGA:G	donor_loss	1.0000
15:39949270:T:A	donor_loss	1.0000
15:39953902:A:AG	acceptor_gain	1.0000
15:39953903:G:GG	acceptor_gain	1.0000
15:39953903:GC:G	acceptor_gain	1.0000
15:39953903:GCAAC:G	acceptor_gain	1.0000
15:39953967:A:T	donor_gain	1.0000
15:39953976:GC:G	donor_gain	1.0000
15:39953977:C:G	donor_gain	1.0000

AlphaMissense

10868 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:39973699:T:C	F590L	1.000
15:39973701:T:A	F590L	1.000
15:39973701:T:G	F590L	1.000
15:39973732:T:C	F601L	1.000
15:39973734:T:A	F601L	1.000
15:39973734:T:G	F601L	1.000
15:39973736:G:A	G602E	1.000
15:39976445:C:A	A617E	1.000
15:39976450:A:G	K619E	1.000
15:39976452:G:C	K619N	1.000
15:39976452:G:T	K619N	1.000
15:39976546:T:C	Y651H	1.000
15:39976558:T:A	W655R	1.000
15:39976558:T:C	W655R	1.000
15:39985878:T:C	L798P	1.000
15:39987984:T:C	M802T	1.000
15:39987985:G:A	M802I	1.000
15:39987985:G:C	M802I	1.000
15:39987985:G:T	M802I	1.000
15:39988008:T:C	L810S	1.000
15:39988011:G:C	R811P	1.000
15:39988083:G:A	G835E	1.000
15:39990282:C:G	H846D	1.000
15:39990283:A:G	H846R	1.000
15:39990284:C:A	H846Q	1.000
15:39990284:C:G	H846Q	1.000
15:39990286:G:C	R847P	1.000
15:39990289:A:C	D848A	1.000
15:39990289:A:G	D848G	1.000
15:39990289:A:T	D848V	1.000

dbSNP variants (sampled 300 via entrez): RS1000026488 (15:39942799 A>T), RS1000041322 (15:39936540 G>A), RS1000147448 (15:40032722 G>A), RS1000156286 (15:40030130 C>A,G,T), RS1000194364 (15:40012605 T>C), RS1000249058 (15:39961105 GA>G,GAA), RS1000267619 (15:40004322 C>T), RS1000292522 (15:39974399 C>A,T), RS1000305967 (15:39994908 A>G), RS1000336507 (15:39950684 A>G), RS1000369834 (15:40010608 A>T), RS1000370085 (15:39994439 C>A,G), RS1000375928 (15:39980629 G>A,T), RS1000396801 (15:40018319 TA>T), RS1000461553 (15:39938124 T>C)

Disease associations

OMIM: gene MIM:609280 | disease phenotypes: MIM:234810, MIM:265450

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary venoocclusive disease 2	Strong	Autosomal recessive
heritable pulmonary arterial hypertension	Supportive	Autosomal dominant
pulmonary venoocclusive disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis	Definitive	AR

Mondo (5): pulmonary venoocclusive disease 2 (MONDO:0009329), pulmonary arterial hypertension (MONDO:0015924), pulmonary venoocclusive disease 1 (MONDO:0020713), heritable pulmonary arterial hypertension (MONDO:0017148), pulmonary venoocclusive disease (MONDO:0009937)

Orphanet (4): Pulmonary capillary hemangiomatosis (Orphanet:199241), Pulmonary arterial hypertension (Orphanet:182090), Pulmonary venoocclusive disease (Orphanet:31837), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000961	Cyanosis
HP:0001698	Pericardial effusion
HP:0001708	Right ventricular failure
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002105	Hemoptysis
HP:0002202	Pleural effusion
HP:0002716	Lymphadenopathy
HP:0002875	Exertional dyspnea
HP:0003493	Antinuclear antibody positivity
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0004890	Elevated pulmonary artery pressure
HP:0005954	Pulmonary capillary hemangiomatosis
HP:0006518	Pulmonary venous occlusion
HP:0010741	Pedal edema
HP:0011462	Young adult onset
HP:0012151	Hemothorax
HP:0012418	Hypoxemia
HP:0012432	Chronic fatigue
HP:0012735	Cough
HP:0025104	Capillary malformation
HP:0025179	Ground-glass opacification
HP:0025180	Centrilobular ground-glass opacification on pulmonary HRCT
HP:0025420	Diffuse alveolar hemorrhage
HP:0030879	Interlobular septal thickening
HP:0030968	Abnormal pulmonary vein morphology
HP:0032230	Cytoplasmic antineutrophil antibody positivity
HP:0045051	Decreased DLCO

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001407_2	Ewing sarcoma	7.000000e-09
GCST001680_5	Corneal curvature	6.000000e-06
GCST002435_1	Body mass index	1.000000e-06
GCST002465_2	Response to haloperidol in psychosis	9.000000e-06
GCST004612_135	High light scatter reticulocyte percentage of red cells	1.000000e-09
GCST004619_17	Reticulocyte fraction of red cells	1.000000e-10
GCST004621_76	Red cell distribution width	3.000000e-16
GCST004630_157	Mean corpuscular hemoglobin	2.000000e-09
GCST006804_118	Red cell distribution width	7.000000e-16
GCST007094_131	Diastolic blood pressure	8.000000e-08
GCST007095_7	Systolic blood pressure	6.000000e-06
GCST007096_74	Pulse pressure	5.000000e-06
GCST007099_54	Systolic blood pressure	2.000000e-10
GCST007267_142	Systolic blood pressure	6.000000e-09
GCST012490_211	Femur bone mineral density x serum urate levels interaction	2.000000e-09
GCST90002385_42	High light scatter reticulocyte count	4.000000e-11
GCST90002386_591	High light scatter reticulocyte percentage of red cells	1.000000e-15
GCST90002390_410	Mean corpuscular hemoglobin	5.000000e-28
GCST90002391_146	Mean corpuscular hemoglobin concentration	1.000000e-14
GCST90002392_423	Mean corpuscular volume	4.000000e-17
GCST90002401_88	Platelet distribution width	3.000000e-24
GCST90002403_476	Red blood cell count	2.000000e-17
GCST90002404_360	Red cell distribution width	1.000000e-24
GCST90013663_54	Alanine aminotransferase levels	6.000000e-26
GCST90013664_54	Aspartate aminotransferase levels	3.000000e-22

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004345	corneal topography
EFO:0004340	body mass index
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004531	urate measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007984	platelet component distribution width
EFO:0004305	erythrocyte count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D011668	Pulmonary Veno-Occlusive Disease	C08.381.780; C14.907.690
C535861	Hemangiomatosis, familial pulmonary capillary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5358 (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: 253,675 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL572881	MOTESANIB	3	4,642
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL558752	RAF-265	2	2,721
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL607707	PELITINIB	2	6,340
CHEMBL1908394	GSK-461364	1	1,093
CHEMBL1908397	KW-2449	1	622
CHEMBL3577124	LY-3009120	1	198

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2412459	Efficacy	3	olanzapine;quetiapine;risperidone;ziprasidone	Schizophrenia
rs2412459	Efficacy	3	haloperidol	Schizophrenia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2412459	EIF2AK4	3	0.00	2	olanzapine;quetiapine;risperidone;ziprasidone;haloperidol

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — GCN2 subfamily

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

Ligand	Action	Affinity	Parameter
compound 39 [PMID: 36127295]	Inhibition	8.3	pIC50
HC-7366	Activation	7.92	pIC50
compound A127 [WO2013110309]	Inhibition	6.52	pIC50

Binding affinities (BindingDB)

232 measured of 334 human assays (505 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2,5-dichloro-N- (3-(2-(((1R,4R)-4- (dimethylamino)cy- clohexyl)amino) quinazolin-6-yl)- 2,4-difluorophenyl)- 3- (hydroxymethyl)ben- zenesulfonamide	IC50	1.11 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
5-chloro-N-[3,5-difluoro-4-[5-fluoro-2-(methylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	1.4 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[8-fluoro-3-(methylamino)isoquinolin-7-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	1.5 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3-fluoro-4-[5-fluoro-2-(methylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	1.6 nM	US-20250340530: GCN2 INHIBITOR (as amended)
trans-(1R,3R)-3-[[6-[2-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-3-fluoro-4-pyridinyl]quinazolin-2-yl]amino]-N-methylcyclopentane-1-carboxamide	KI	1.6 nM	US-20250340530: GCN2 INHIBITOR (as amended)
N-(3-(2- (((1R,4R)-4- aminocyclohexyl) amino)quinazolin- 6-yl)-2,4- difluorophenyl)- 5-chloro-2- methoxypyridine- 3-sulfonamide	IC50	1.64 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
Staurosporine	KD	1.7 nM
US20250340530, Example 1	KI	1.7 nM	US-20250340530: GCN2 INHIBITOR (as amended)
N-[4-(2-amino-5-fluoroquinazolin-6-yl)-3-fluoro-2-pyridinyl]-5-chloro-2-methoxypyridine-3-sulfonamide	KI	1.9 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[5-fluoro-2-(2-methoxyethylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	1.9 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3-fluoro-4-[5-fluoro-2-(oxetan-3-ylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	1.9 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[2,4-difluoro-3-[2-(2-hydroxyethylamino)quinazolin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide	KI	1.9 nM	US-20250340530: GCN2 INHIBITOR (as amended)
trans-(1R,3R)-3-[[6-[2-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-3-fluoro-4-pyridinyl]-5-fluoroquinazolin-2-yl]amino]-N-methylcyclopentane-1-carboxamide	KI	2 nM	US-20250340530: GCN2 INHIBITOR (as amended)
(1R,3R)-3-((6-(3- ((2,5-dichloro-3- (hydroxymethyl)phe- nyl)sulfonamido)- 2,6- difluorophenyl)quina- zolin-2- yl)amino)cyclopent- ane-1- carboxamide	IC50	2.12 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
5-chloro-N-[3,5-difluoro-4-[2-(methylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	2.2 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[2-(oxetan-3-ylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	2.2 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3-fluoro-4-[2-(1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]-2-pyridinyl]-2-methoxy-6-methylpyridine-3-sulfonamide	KI	2.28 nM	US-20250129068: 4-(2-PYRAZOLO[3,4-B]PYRIDINE-5-YL)ETHYNYL-2-PYRIDINE DERIVATIVES USEFUL AS GCN2 INHIBITORS
5-chloro-N-[3,5-difluoro-4-[5-fluoro-2-(oxetan-3-ylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	2.3 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-(3-(2- (((1R,4R)-4- (dimethylamino)cy- clohexyl)amino) quinazolin-6-yl)- 2,4- difluorophenyl)- 2- methoxypyridine- 3-sulfonamide	IC50	2.35 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
N-[4-(2-amino-5-fluoroquinazolin-6-yl)-3,5-difluoro-2-pyridinyl]-5-chloro-2-methoxypyridine-3-sulfonamide	KI	2.4 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3-fluoro-4-[2-(1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]-2-pyridinyl]-2-methylpyridine-3-sulfonamide	KI	2.49 nM	US-20250129068: 4-(2-PYRAZOLO[3,4-B]PYRIDINE-5-YL)ETHYNYL-2-PYRIDINE DERIVATIVES USEFUL AS GCN2 INHIBITORS
5-chloro-N-[3,5-difluoro-4-[5-fluoro-2-(2-hydroxyethylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	2.5 nM	US-20250340530: GCN2 INHIBITOR (as amended)
trans-(1R,3R)-3-[[6-[2-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-3,5-difluoro-4-pyridinyl]quinazolin-2-yl]amino]-N-methylcyclopentane-1-carboxamide	KI	2.6 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3-fluoro-4-[8-fluoro-3-(methylamino)isoquinolin-7-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	2.6 nM	US-20250340530: GCN2 INHIBITOR (as amended)
US20250340530, Example 25	KI	2.6 nM	US-20250340530: GCN2 INHIBITOR (as amended)
2,5-dichloro-N- (2,4-difluoro-3- (2-(((1R,3R)-3- (((2- methoxyethyl)ami- no)methyl)cyclopent- yl)amino)quina- zolin-6- yl)phenyl)-3- (hydroxymethyl)ben- zenesulfonamide	IC50	2.63 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
N-[4-(3-amino-8-fluoroisoquinolin-7-yl)-3-fluoro-2-pyridinyl]-5-chloro-2-methoxypyridine-3-sulfonamide	KI	3 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-(2,4- difluoro-3-(2- (((1R,4R)-4- (methylamino)cyclo- hexyl)amino)quina- zolin-6- yl)phenyl)-2- methoxypyridine- 3-sulfonamide	IC50	3.23 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
N-[4-(2-amino-5-chloroquinazolin-6-yl)-3-fluoro-2-pyridinyl]-5-chloro-2-methoxypyridine-3-sulfonamide	KI	3.3 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-(3-(2- (((1R,4R)-4- (dimethylamino)cy- clohexyl)amino) quinazolin-6-yl)- 2,4-difluorophenyl)- 2-methylpyridine- 3-sulfonamide	IC50	3.36 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
(1R,3R)-3-((6-(3- ((5-chloro-2- methoxypyridine)- 3-sulfonamido)- 2,6- difluorophenyl)quinaz- zolin-2- yl)amino)cyclopent- ane-1- carboxamide	IC50	3.39 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
5-chloro-N-[3,5-difluoro-4-[3-(methylamino)isoquinolin-7-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	3.4 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[3-(2-methoxyethylamino)isoquinolin-7-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	3.4 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3-fluoro-4-[8-fluoro-3-(2-methoxyethylamino)isoquinolin-7-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	3.7 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[8-fluoro-3-(2-methoxyethylamino)isoquinolin-7-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	3.9 nM	US-20250340530: GCN2 INHIBITOR (as amended)
(1R,4R)-4-((6-(3- ((2,5-dichloro-3- (hydroxymethyl)phe- nyl)sulfonamido)- 2,6- difluorophenyl)quina- zolin-2- yl)amino)-N-(2- (dimethylamino)eth- yl)cyclohexane- 1-carboxamide	IC50	3.94 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
5-chloro-N-(3-(2- (((1R,4R)-4- (dimethylamino)cy- clohexyl)amino)- 8- ethylquinazolin- 6-yl)-2,4- difluorophenyl)- 2- methoxypyridine- 3-sulfonamide	IC50	3.95 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
5-chloro-N-(2,4- difluoro-3-(2- (((1R,3R)-3-(((2- methoxyethyl)ami- no)methyl)cyclopent- yl)amino)quina- zolin-6- yl)phenyl)-2- methoxypyridine- 3-sulfonamide	IC50	3.96 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
(2R,4S)-4-((6-(3- ((5-chloro-2- methoxypyridine)- 3-sulfonamido)- 2,6- difluorophenyl)quina- zolin-2- yl)amino)-N-(2- methoxyethyl)pyr- rolidine-2- carboxamide	IC50	4.18 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
5-fluoro-N-[3-fluoro-4-[2-(1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]-2-pyridinyl]-2-methylpyridine-3-sulfonamide	KI	4.19 nM	US-20250129068: 4-(2-PYRAZOLO[3,4-B]PYRIDINE-5-YL)ETHYNYL-2-PYRIDINE DERIVATIVES USEFUL AS GCN2 INHIBITORS
US20250340530, Example 24	KI	4.4 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-fluoro-N-[3-fluoro-4-[2-(1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	4.42 nM	US-20250129068: 4-(2-PYRAZOLO[3,4-B]PYRIDINE-5-YL)ETHYNYL-2-PYRIDINE DERIVATIVES USEFUL AS GCN2 INHIBITORS
5-chloro-N-[3-fluoro-4-[5-fluoro-2-(2-methoxyethylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	4.5 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	4.7 nM	US-20250340530: GCN2 INHIBITOR (as amended)
5-chloro-N-[3,5-difluoro-4-[2-(2-methoxyethylamino)quinazolin-6-yl]-2-pyridinyl]-2-methoxypyridine-3-sulfonamide	KI	4.9 nM	US-20250340530: GCN2 INHIBITOR (as amended)
N-(3-(2- (((1R,4R)-4- aminocyclohexyl) amino)-8- ethylquinazolin- 6-yl)-2,4- difluorophenyl)- 5-chloro-2- methoxypyridine- 3-sulfonamide	IC50	5.13 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
(2R,4S)-4-((6-(3- ((2,5-dichloro-3- (hydroxymethyl)phe- nyl)sulfonamido)- 2,6- difluorophenyl)quin- zolin-2- yl)amino)-N-(2- methoxyethyl)pyr- rolidine-2- carboxamide	IC50	5.43 nM	US-20250263400: GCN2 MODULATOR COMPOUNDS
N-[3-fluoro-4-[2-(1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]-2-pyridinyl]-2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamide	KI	5.78 nM	US-20250129068: 4-(2-PYRAZOLO[3,4-B]PYRIDINE-5-YL)ETHYNYL-2-PYRIDINE DERIVATIVES USEFUL AS GCN2 INHIBITORS
N-[3-fluoro-4-[2-(1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]-2-pyridinyl]-2-methoxy-5-methylpyridine-3-sulfonamide	KI	6.6 nM	US-20250129068: 4-(2-PYRAZOLO[3,4-B]PYRIDINE-5-YL)ETHYNYL-2-PYRIDINE DERIVATIVES USEFUL AS GCN2 INHIBITORS

ChEMBL bioactivities

530 potent at pChembl≥5 of 530 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5200118
8.60	IC50	2.5	nM	CHEMBL5571568
8.52	IC50	3	nM	CHEMBL5202342
8.48	Kd	3.3	nM	R-406
8.40	IC50	4	nM	CHEMBL5427321
8.39	Kd	4.1	nM	LESTAURTINIB
8.30	IC50	5	nM	CHEMBL3407849
8.30	IC50	5	nM	CHEMBL5209076
8.30	IC50	5	nM	CHEMBL5179922
8.30	IC50	5	nM	CHEMBL5190023
8.21	IC50	6.1	nM	CHEMBL5574976
8.10	IC50	8	nM	CHEMBL5208600
8.10	IC50	8	nM	CHEMBL5196751
8.05	IC50	9	nM	CHEMBL5200118
8.00	IC50	10	nM	CHEMBL3407851
8.00	IC50	10	nM	CHEMBL5193210
7.96	IC50	11	nM	CHEMBL5202445
7.92	IC50	12	nM	CHEMBL3407850
7.92	IC50	12	nM	CHEMBL5569981
7.89	IC50	13	nM	CHEMBL5571377
7.89	EC50	13	nM	CHEMBL5571568
7.85	IC50	14	nM	CHEMBL5591595
7.82	IC50	15	nM	CHEMBL5201930
7.82	IC50	15	nM	CHEMBL5579682
7.82	IC50	15	nM	CHEMBL5590796
7.80	IC50	16	nM	CHEMBL5170361
7.80	IC50	16	nM	CHEMBL5172690
7.80	IC50	16	nM	CHEMBL5190023
7.80	IC50	16	nM	CHEMBL5393957
7.80	Kd	16	nM	STAUROSPORINE
7.80	Kd	16	nM	CGP-52421
7.77	IC50	17	nM	CHEMBL5199369
7.73	IC50	18.6	nM	CHEMBL5437361
7.70	IC50	20	nM	CHEMBL5179922
7.68	IC50	21	nM	CHEMBL5195519
7.68	IC50	21	nM	CHEMBL5180017
7.68	IC50	21	nM	CHEMBL5199369
7.64	IC50	23	nM	CHEMBL5199283
7.60	IC50	25	nM	CHEMBL5180017
7.60	IC50	25	nM	CHEMBL5172690
7.58	Kd	26	nM	CHEMBL386051
7.57	IC50	27	nM	CHEMBL5201758
7.54	IC50	29	nM	CHEMBL5195933
7.54	IC50	29	nM	CHEMBL5193210
7.48	IC50	33	nM	CHEMBL5208600
7.46	IC50	35	nM	CHEMBL5196751
7.44	IC50	36	nM	CHEMBL3407852
7.41	IC50	39	nM	CHEMBL5593998
7.41	IC50	39	nM	CHEMBL5575532
7.41	Kd	39	nM	MIDOSTAURIN

PubChem BioAssay actives

167 with measured affinity, of 430 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
cis-(1R,3R)-3-[[3-bromo-1-[3-(2-methylsulfonylethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0020	uM
5-chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0025	uM
3-bromo-N-(1-piperidin-4-ylpyrazol-4-yl)-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-amine	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0030	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	624810: Binding constant for GCN2(Kin.Dom.2,S808G) kinase domain	kd	0.0033	uM
4-N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]-2-methylbenzene-1,4-diamine	1995231: Inhibition of human recombinant GCN2 using eIF2alpha as substrate	ic50	0.0040	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	507962: Binding affinity to GCN2 Kin.Dom.2, S808G mutant	kd	0.0041	uM
1-methyl-4-[4-methyl-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-2,5-diphenylpyrazol-3-one	1196989: Inhibition of human C-terminal His-tagged GCN2 expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0050	uM
trans-(1R,3R)-3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-N-(2-methoxyethyl)cyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0050	uM
cis-(1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0050	uM
3-chloro-N-(1-piperidin-4-ylpyrazol-4-yl)-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-amine	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0050	uM
5-chloro-N-[2,4-difluoro-3-[7-fluoro-3-(1H-imidazol-2-yl)-2H-indazol-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0061	uM
cis-(1R,3R)-3-[[3-bromo-1-[3-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0080	uM
cis-(1R,3R)-3-[[3-bromo-1-[3-cyano-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0080	uM
4-[4-chloro-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196989: Inhibition of human C-terminal His-tagged GCN2 expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0100	uM
cis-(1R,3R)-3-[[3-bromo-1-[3-(2-cyanoethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0100	uM
3-methyl-N-(1-piperidin-4-ylpyrazol-4-yl)-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-amine	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0110	uM
4-[4-amino-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196989: Inhibition of human C-terminal His-tagged GCN2 expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0120	uM
6-[3-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0120	uM
6-[3-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0130	uM
2-[3-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0140	uM
cis-(1R,3R)-3-[[1-[3-(2-aminoethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]-3-bromopyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0150	uM
6-[3-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-2,6-difluorophenyl]-7-fluoro-N-methyl-2H-indazole-3-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0150	uM
6-[3-[(5-chloro-2-methoxy-3-pyridinyl)sulfonylamino]-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0150	uM
cis-(1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0160	uM
cis-(1R,3R)-3-[[3-bromo-1-[3-(2-hydroxyethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0160	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	436020: Binding constant for GCN2(Kin.Dom.2,S808G) kinase domain	kd	0.0160	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	507962: Binding affinity to GCN2 Kin.Dom.2, S808G mutant	kd	0.0160	uM
3-(4-ethoxyphenyl)-N-[1-(oxan-4-yl)pyrazol-4-yl]triazolo[4,5-d]pyrimidin-5-amine	1995230: Inhibition of human GCN2 (unknown origin)	ic50	0.0160	uM
cis-(1R,3R)-3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0170	uM
3-(4-ethoxyphenyl)-N-(1-ethylpyrazol-4-yl)triazolo[4,5-d]pyrimidin-5-amine	1995232: Inhibition of human recombinant GCN2 by P-ATP kinase assay	ic50	0.0186	uM
3-bromo-N-[(1R,3R)-3-(1H-imidazol-2-yl)cyclopentyl]-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-amine	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0210	uM
trans-(1R,3R)-3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-N-methylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0210	uM
N-(1-ethylpyrazol-4-yl)-3-methyl-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-amine	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0230	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624810: Binding constant for GCN2(Kin.Dom.2,S808G) kinase domain	kd	0.0260	uM
cis-(1R,3R)-3-[[3-bromo-1-[4-(2-methyl-1,3-thiazol-5-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0270	uM
cis-(1R,3R)-3-[[3-bromo-1-[3-[2-(dimethylamino)ethyl]-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0290	uM
4-[2-amino-3-[5-fluoro-2-(methylamino)quinazolin-7-yl]oxy-4-methylbenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196989: Inhibition of human C-terminal His-tagged GCN2 expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0360	uM
6-[2,6-difluoro-3-[(5-fluoro-2-methyl-3-pyridinyl)sulfonylamino]phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0390	uM
(6R)-6-[2,6-difluoro-3-[(5-fluoro-2-methoxy-3-pyridinyl)sulfonylamino]phenyl]-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0390	uM
Midostaurin	436020: Binding constant for GCN2(Kin.Dom.2,S808G) kinase domain	kd	0.0390	uM
3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-N-(2-methoxyethyl)cyclobutane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0400	uM
4-[2-amino-4-methyl-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196989: Inhibition of human C-terminal His-tagged GCN2 expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0420	uM
4-[2-amino-3-[5-chloro-2-(methylamino)quinazolin-7-yl]oxy-4-methylbenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196989: Inhibition of human C-terminal His-tagged GCN2 expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0420	uM
trans-(1R,3R)-3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-N-methylcyclopentane-1-sulfonamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0430	uM
6-[2,6-difluoro-3-[(5-fluoro-2-methoxy-3-pyridinyl)sulfonylamino]phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide	2103348: Inhibition of GCN2 (unknown origin) using GFP-eIF2alpha as substrate incubated for 1.5 hrs in presence of ATP by plate reader analysis	ic50	0.0430	uM
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	436020: Binding constant for GCN2(Kin.Dom.2,S808G) kinase domain	kd	0.0550	uM
N-[(1R,3R)-3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]cyclopentyl]-2-methoxyethanesulfonamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0550	uM
4-[6-[(1-ethylpyrazol-4-yl)amino]-3-methylpyrazolo[3,4-d]pyrimidin-1-yl]benzonitrile	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0560	uM
cis-(1R,3R)-3-[[3-bromo-1-[3-methylsulfonyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0610	uM
cis-(1S,3R)-3-[(3-bromo-1-quinolin-6-ylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-N-(2-methoxyethyl)cyclopentane-1-carboxamide	1856705: Inhibition of GCN2 (unknown origin)	ic50	0.0610	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	3
Aflatoxin B1	affects expression, increases expression	3
sodium arsenite	decreases expression, increases abundance	2
epigallocatechin gallate	affects cotreatment, affects reaction, increases cleavage, decreases phosphorylation, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	increases expression, decreases expression	2
Cisplatin	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
borrelidin	increases activity	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
nobiletin	decreases phosphorylation, affects cotreatment, affects reaction, increases cleavage	1
sodium arsenate	decreases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
cupric oxide	decreases expression	1
avobenzone	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Irinotecan	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1

ChEMBL screening assays

170 unique, capped per target: 170 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1049979	Binding	Binding affinity to GCN2 kinase domain 2 S808G mutant assessed as percentage of kinase remaining bound to the bead at 1 uM by T7 phage display based binding assay	Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). — J Med Chem

Cellosaurus cell lines

14 cell lines: 12 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2WC	Abcam HEK293T EIF2AK4 KO 1	Transformed cell line	Female
CVCL_B2WD	Abcam HEK293T EIF2AK4 KO 2	Transformed cell line	Female
CVCL_B7X4	Abcam Raji EIF2AK4 KO	Cancer cell line	Male
CVCL_B9XQ	Abcam THP-1 EIF2AK4 KO	Cancer cell line	Male
CVCL_C6ZK	Abcam PC-3 EIF2AK4 KO	Cancer cell line	Male
CVCL_E0X4	Ubigene L-02 EIF2AK4 KO	Cancer cell line	Female
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_E1NV	HAP1 EIF2AK3 (-) EIF2AK4 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial