EIF2S1

Summary

EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha, HGNC:3265) is a protein-coding gene on chromosome 14q23.3, encoding Eukaryotic translation initiation factor 2 subunit 1 (P05198). Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The translation initiation factor EIF2 catalyzes the first regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA to 40S ribosomal subunits. Binding occurs as a ternary complex of methionyl-tRNA, EIF2, and GTP. EIF2 is composed of 3 nonidentical subunits, the 36-kD EIF2-alpha subunit (EIF2S1), the 38-kD EIF2-beta subunit (EIF2S2; MIM 603908), and the 52-kD EIF2-gamma subunit (EIF2S3; MIM 300161). The rate of formation of the ternary complex is modulated by the phosphorylation state of EIF2-alpha (Ernst et al., 1987 [PubMed 2948954]).

Source: NCBI Gene 1965 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 109 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_004094

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3265
Approved symbol	EIF2S1
Name	eukaryotic translation initiation factor 2 subunit alpha
Location	14q23.3
Locus type	gene with protein product
Status	Approved
Aliases	EIF-2alpha, EIF2A
Ensembl gene	ENSG00000134001
Ensembl biotype	protein_coding
OMIM	603907
Entrez	1965

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 2 retained_intron

ENST00000256383, ENST00000466499, ENST00000554332, ENST00000555876, ENST00000556724, ENST00000557310, ENST00000858842, ENST00000858843, ENST00000858844, ENST00000858845, ENST00000858846, ENST00000916140, ENST00000916141, ENST00000950583, ENST00000950584

RefSeq mRNA: 1 — MANE Select: NM_004094 NM_004094

CCDS: CCDS9781

Canonical transcript exons

ENST00000256383 — 8 exons

Exon	Start	End
ENSE00000911628	67374468	67374547
ENSE00000911630	67376439	67376590
ENSE00000911632	67380659	67380765
ENSE00000911634	67381593	67381690
ENSE00000911635	67382447	67382590
ENSE00001168441	67383315	67386516
ENSE00001931166	67360328	67360456
ENSE00003675760	67364767	67365008

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 97.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.8203 / max 1817.1032, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140218	68.3224	1824
140219	1.4609	904
140216	1.1829	813
140220	0.5569	292
140217	0.2972	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	97.83	gold quality
monocyte	CL:0000576	97.21	gold quality
gingival epithelium	UBERON:0001949	97.03	gold quality
adrenal tissue	UBERON:0018303	96.88	gold quality
mononuclear cell	CL:0000842	96.85	gold quality
leukocyte	CL:0000738	96.66	gold quality
gingiva	UBERON:0001828	96.63	gold quality
gastrocnemius	UBERON:0001388	96.48	gold quality
ganglionic eminence	UBERON:0004023	96.37	gold quality
pancreas	UBERON:0001264	96.30	gold quality
stromal cell of endometrium	CL:0002255	96.24	gold quality
heart right ventricle	UBERON:0002080	96.21	gold quality
muscle of leg	UBERON:0001383	96.18	gold quality
squamous epithelium	UBERON:0006914	96.16	gold quality
vermiform appendix	UBERON:0001154	96.13	gold quality
cortical plate	UBERON:0005343	96.08	gold quality
esophagus squamous epithelium	UBERON:0006920	96.03	gold quality
ventricular zone	UBERON:0003053	96.00	gold quality
body of pancreas	UBERON:0001150	95.97	gold quality
esophagus mucosa	UBERON:0002469	95.93	gold quality
rectum	UBERON:0001052	95.61	gold quality
esophagus	UBERON:0001043	95.60	gold quality
caecum	UBERON:0001153	95.60	gold quality
epithelium of esophagus	UBERON:0001976	95.60	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.54	gold quality
popliteal artery	UBERON:0002250	95.53	gold quality
tibial artery	UBERON:0007610	95.52	gold quality
mucosa of transverse colon	UBERON:0004991	95.48	gold quality
heart left ventricle	UBERON:0002084	95.45	gold quality
artery	UBERON:0001637	95.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ENAD-21	yes	1264.69
E-GEOD-93593	yes	8.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ATF4	Unknown
HBG1	Activation
HBG2	Activation

Upstream regulators (CollecTRI, top): NR1I2, NRF1

miRNA regulators (miRDB)

177 targeting EIF2S1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Crystal structure of the N-terminal segment of human eukaryotic translation initiation factor 2alpha (PMID:11859078)
• increased expression of both eIF-4E and eIF-2alpha in aggresive thyroid carcinoma compared to conventional papillary carcinoma suggesting a role in the progression of thyroid cancer (PMID:12186496)
• eIF2alpha phosphorylation plays a role in hypoxia-induced translational attenuation (PMID:12370288)
• that phosphorylation of eIF2alpha is associated with the degeneration of neurons in Alzheimer’s disease (PMID:12499843)
• P58(IPK) is an important component of a negative feedback loop used by the cell to inhibit eIF2alpha signaling, and thus attenuate the unfolded protein response. (PMID:12601012)
• Nitric oxide participates in the phosphorylation of eIF2alpha since nNOS processes are closely related to eIF2alpha(P) positive cells in temporal lobe epilepsy with hippocampal sclerosis (PMID:12686399)
• phosphorylation of eIF2alpha during early brain reperfusion is carried out by PERK, these findings suggest that there is prolonged activation of the unfolded protein response in the reperfused brain. (PMID:12687390)
• High levels of Epstein-Barr virus LMP1 correlated with high levels of phosphorylation of eIF2 alpha in EBV infected lymphoblasts (PMID:14747531)
• Results demonstrate a role of the oncogenic human papillomavirus E6 protein in apoptotic signaling induced by interferon-inducible protein kinase PKR and eukaryotic translation initiation factor 2-alpha phosphorylation. (PMID:15060162)
• phosphorylation of the alpha-subunit of the canonical initiation factor eIF-2 is increased at G2/M; phosphorylation of eIF-2alpha has a permissive effect on the efficiency of the PITSLRE IRES (PMID:15330758)
• Results indicate an evolutionary lineage of translation initiation factor eIF2alpha/gamma from the functionally related elongation factor eEF1Balpha/eEF1A complex. (PMID:15341733)
• multiple domains in I-1 target cellular PP1 complexes, and I-1 has a role as a cellular regulator of eIF2alpha phosphorylation (PMID:15345721)
• phosphorylation affected by cowpox virus CP77 gene expressed in vaccinia virus in Hela cells (PMID:15476887)
• EIF-2 phosphorylation regulated by gamma(1)34.5 protein durign produtive HSV-1 infection (PMID:15650164)
• Given that eEF2 phosphorylation inhibits eEF2 activity and mRNA translation, these findings suggest that the inhibition of protein synthesis in contracting skeletal muscle is due to the Ca(2)(+)-induced stimulation of eEF2 kinase. (PMID:16210351)
• Phosphorylation of eIF2 alpha in vitro is not significantly different in the presence and absence of the other subunits (PMID:16289913)
• Tyrosine phosphorylation acts as a molecular switch to full-scale activation of the eIF2alpha RNA-dependent protein kinase. (PMID:16373505)
• Data report that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2alpha complex. (PMID:16418533)
• heat-shock and lead toxicity induced heme-regulated-eIF-2alpha kinase or -inhibitor (HRI) promoter activity by 2- to 3-fold. Hemin, a suppressor of HRI kinase activity, downregulated HRI promoter activity and stimulated hemoglobin synthesis. (PMID:16500424)
• Our results demonstrate that Ebp1 is a new dsRNA-binding protein that acts as a cellular inhibitor of eIF2alpha phosphorylation suggesting that it could be involved in protein translation control (PMID:16631606)
• Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosis (PMID:16717090)
• We propose that SG modeling can occur via both eIF2alpha phosphorylation-dependent and -independent pathways that target translation initiation. (PMID:16870703)
• functional eIF2alpha played an essential role in PS-341-induced Noxa expression (PMID:16928686)
• The underlying biochemical mechanism of the activation of PKR via PACT phosphorylation at specific activation domain residues is reported as the major mode of transmission of cellular stress response to PKR. (PMID:16982605)
• Novel polycythemia vera (PV)-associated tumor antigen PV65 (eIF-2alpha) elicits IgG antibody reactions in a subset of PV patients but not in healthy donors, suggesting that it is an authentic tumor antigens. (PMID:17113348)
• Caprin-1/G3BP-1 complex is likely to regulate the transport and translation of mRNAs of proteins involved with synaptic plasticity in neurons (PMID:17210633)
• EIF2alpha became highly phosphorylated by increased production of Abeta was substantiated in brain tissues of AD patients. (PMID:17393484)
• eIF-2alpha is phosphorylated during hypoxic treatment but only the eIF-2alpha phosphorylation correlates with the translational repression. (PMID:17488873)
• stress-induced phosphorylation of eIF2 alpha is directly coupled to mitochondrial apoptosis regulation via translational repression of MCL-1 (PMID:17553788)
• the induction of the PKR/eIF2alpha cellular response may be a previously unrecognized general feature of at least the Dependovirus genus of the Parvovirinae (PMID:17715234)
• ABC50 N-terminal region interacts with eukaryotic initiation factor eIF2 and is a target for regulatory phosphorylation by CK2 (PMID:17894550)
• PKR and PKR-like endoplasmic reticulum kinase induce the proteasome-dependent degradation of cyclin D1 via a mechanism requiring eukaryotic initiation factor 2alpha phosphorylation (PMID:18063576)
• Both nonalcoholic fatty liver and nonalcoholic steatohepatitis are associated with eIF-2alpha phosphorylation. (PMID:18082745)
• ATF4 contributes to basal ATF5 transcription, and eIF2 kinases direct the translational expression of multiple transcription regulators by a mechanism involving delayed translation reinitiation (PMID:18195013)
• Both eIF-4E and eIF-2 alpha are strongly expressed in neoplastic cells of Hodgkin lymphoma. (PMID:18234281)
• MEK functions to enhance GCN2-dependent eIF2alpha phosphorylation rather than suppressing dephosphorylation (PMID:18287093)
• a switch from the conventional eukaryotic mode of translation initiation to the eIF2-independent mechanism occurs when eIF2 is inactivated by phosphorylation under stress conditions (PMID:18604219)
• These findings suggest that alpha and beta subunits of eIF2 interact with each other and the beta-subunit plays a critical role both in the regulation and function of eIF2. (PMID:18639529)
• PC2, but not pathogenic mutants E837X and R872X, represses cell proliferation through promoting the phosphorylation of eukaryotic translation initiation factor eIF2alpha by pancreatic ER-resident eIF2alpha kinase (PERK). (PMID:18664456)
• Proteasomal but not lysosomal inhibitors enhanced GADD34 stability and eukaryotic initiation factor 2alpha (eIF-2alpha) dephosphorylation, a finding consistent with GADD34’s role in assembling an eIF-2alpha phosphatase (PMID:18794359)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2s1a	ENSDARG00000005827
danio_rerio	eif2s1b	ENSDARG00000052178
mus_musculus	Eif2s1	ENSMUSG00000021116
rattus_norvegicus	Eif2s1	ENSRNOG00000009432
drosophila_melanogaster	eIF2alpha	FBGN0261609
caenorhabditis_elegans	eif-2alpha	WBGENE00021351

Protein

Protein identifiers

Eukaryotic translation initiation factor 2 subunit 1 — P05198 (reviewed: P05198)

Alternative names: Eukaryotic translation initiation factor 2 subunit alpha

All UniProt accessions (4): P05198, G3V4T5, H0YJS4, Q53XC0

UniProt curated annotations — full annotation on UniProt →

Function. Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S pre-initiation complex (43S PIC). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex. In order for eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP by way of a reaction catalyzed by eIF2B. EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stress: phosphorylation by metabolic-stress sensing protein kinases (EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2) in response to stress converts EIF2S1/eIF2-alpha in a global protein synthesis inhibitor, leading to an attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming. EIF2S1/eIF2-alpha also acts as an activator of mitophagy in response to mitochondrial damage: phosphorylation by EIF2AK1/HRI promotes relocalization to the mitochondrial surface, thereby triggering PRKN-independent mitophagy.

Subunit / interactions. Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain. eIF2 is member of the 43S pre-initiation complex (43S PIC). eIF2 forms a complex with at least CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Interaction with METAP2 protects EIF2S1 from inhibitory phosphorylation. Interacts with ABCF1 isoform 2. Associates with ribosomes. Interacts with DDX3X in an RNA-independent manner. Interacts with CDC123. (Microbial infection) Interacts with rotavirus A non-structural protein 2; this interaction probably plays a role in the sequestration of IF2A in viral factories. Interacts with rotavirus A non-structural protein 5; this interaction probably plays a role in its sequestration in viral factories.

Subcellular location. Cytoplasm. Stress granule. Cytosol. Mitochondrion.

Post-translational modifications. Phosphorylation at Ser-49 and Ser-52 stabilizes the eIF-2/GDP/eIF2B complex and prevents GDP/GTP exchange reaction, thus impairing the recycling of eIF-2 between successive rounds of initiation and leading to global inhibition of translation, while concomitantly initiating the preferential translation of integrated stress response (ISR)-specific mRNAs. Substrate for at least 4 kinases: EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2. Phosphorylation on Ser-52 by the EIF2AK4/GCN2 protein kinase occurs in response to amino acid starvation and UV irradiation. Phosphorylation at Ser-52 by the EIF2AK3/PERK protein kinase occurs in response to the unfolded protein response. Phosphorylation at Ser-52 by EIF2AK1/HRI in response to mitochondrial damage promotes relocalization to the mitochondrial surface. (Microbial infection) Phosphorylation by vaccinia virus protein E3 and rotavirus A stabilizes the eIF-2/GDP/eIF2B complex and prevents GDP/GTP exchange reaction, thus impairing the recycling of eIF-2 between successive rounds of initiation and leading to global inhibition of translation.

Activity regulation. Activity is regulated by phosphorylation at Ser-49 and Ser-52, which stabilizes the eIF2/GDP/eIF2B complex and prevents the eIF2B-mediated exchange of GDP for GTP, thereby preventing the formation of the 43S pre-initiation complex (43S PIC). This results in the global attenuation of 5’ cap-dependent protein synthesis and concomitant translation of ISR-specific mRNAs that contain a short upstream open reading frame (uORF) in their 5’ UTR, such as ATF4, ATF5, DDIT3/CHOP and PPP1R15A/GADD34.

Induction. Up-regulated upon endoplasmic reticulum stress.

Similarity. Belongs to the eIF-2-alpha family.

RefSeq proteins (1): NP_004085* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003029	S1_domain	Domain
IPR011488	TIF_2_asu	Family
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR024054	TIF2_asu_middle_sf	Homologous_superfamily
IPR024055	TIF2_asu_C	Homologous_superfamily
IPR044126	S1_IF2_alpha	Domain

Pfam: PF00575, PF07541

Enzyme classification (BRENDA):

• EC 3.6.5.3 — protein-synthesizing GTPase (BRENDA: 45 organisms, 101 substrates, 61 inhibitors, 66 Km, 48 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0003–0.27	53
ATP	0.12–0.2	2

UniProt features (39 total): strand 13, helix 11, modified residue 6, turn 3, mutagenesis site 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

33 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1KL9	X-RAY DIFFRACTION	1.9
8PPL	ELECTRON MICROSCOPY	2.65
9HVE	ELECTRON MICROSCOPY	2.7
7F66	ELECTRON MICROSCOPY	2.76
9QC6	ELECTRON MICROSCOPY	2.83
6ZP4	ELECTRON MICROSCOPY	2.9
6O85	ELECTRON MICROSCOPY	3.03
6O9Z	ELECTRON MICROSCOPY	3.03
9NB9	ELECTRON MICROSCOPY	3.03
9HVD	ELECTRON MICROSCOPY	3.04
8PJ4	ELECTRON MICROSCOPY	3.2
6O81	ELECTRON MICROSCOPY	3.21
8QZZ	X-RAY DIFFRACTION	3.35
8PJ1	ELECTRON MICROSCOPY	3.4
8PJ2	ELECTRON MICROSCOPY	3.4
7A09	ELECTRON MICROSCOPY	3.5
7SYS	ELECTRON MICROSCOPY	3.5
8OZ0	ELECTRON MICROSCOPY	3.5
7F67	ELECTRON MICROSCOPY	3.59
7SYR	ELECTRON MICROSCOPY	3.6
6ZMW	ELECTRON MICROSCOPY	3.7
7QP7	ELECTRON MICROSCOPY	3.7
8PJ3	ELECTRON MICROSCOPY	3.7
6YBV	ELECTRON MICROSCOPY	3.8
7D45	ELECTRON MICROSCOPY	3.8
9HVF	ELECTRON MICROSCOPY	3.8
7NZM	ELECTRON MICROSCOPY	3.96
7D44	ELECTRON MICROSCOPY	4
6K71	ELECTRON MICROSCOPY	4.3
7D43	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05198-F1	77.87	0.02

Functional residue map

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

Post-translational modifications (6): 49, 52, 141, 158, 279, 281

Mutagenesis-validated functional residues (2):

Position	Phenotype
52	abolished phosphorylation by eif2ak1/hri in response to stress. abolished relocalization to the mitochondrial surface in
52	mimics phosphorylation; promotes relocalization to the mitochondrial surface in response to mitochondrial damage.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-381042	PERK regulates gene expression
R-HSA-382556	ABC-family protein mediated transport
R-HSA-72649	Translation initiation complex formation
R-HSA-72695	Formation of the ternary complex, and subsequently, the 43S complex
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit
R-HSA-72731	Recycling of eIF2:GDP
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency
R-HSA-9833482	PKR-mediated signaling
R-HSA-9840373	Cellular response to mitochondrial stress

MSigDB gene sets: 509 (showing top): GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, BIOCARTA_RNA_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_RESPONSE_TO_ACID_CHEMICAL, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN

GO Biological Process (19): mitophagy (GO:0000423), translational initiation (GO:0006413), negative regulation of translational initiation in response to stress (GO:0032057), stress granule assembly (GO:0034063), cellular response to amino acid starvation (GO:0034198), cellular response to oxidative stress (GO:0034599), cellular response to heat (GO:0034605), cellular response to UV (GO:0034644), response to endoplasmic reticulum stress (GO:0034976), regulation of translation in response to endoplasmic reticulum stress (GO:0036490), PERK-mediated unfolded protein response (GO:0036499), regulation of translational initiation in response to stress (GO:0043558), HRI-mediated signaling (GO:0140468), response to kainic acid (GO:1904373), response to manganese-induced endoplasmic reticulum stress (GO:1990737), positive regulation of type B pancreatic cell apoptotic process (GO:2000676), translation (GO:0006412), regulation of translation (GO:0006417), mitochondrial respirasome assembly (GO:0097250)

GO Molecular Function (5): RNA binding (GO:0003723), translation initiation factor activity (GO:0003743), ribosome binding (GO:0043022), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (12): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), eukaryotic translation initiation factor 2 complex (GO:0005850), cytoplasmic stress granule (GO:0010494), membrane (GO:0016020), eukaryotic 48S preinitiation complex (GO:0033290), translation initiation ternary complex (GO:0044207), synapse (GO:0045202), extracellular exosome (GO:0070062), glial limiting end-foot (GO:0097451)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Cap-dependent Translation Initiation	4
Cellular responses to stress	2
Eukaryotic Translation Initiation	1
Unfolded Protein Response (UPR)	1
Transport of small molecules	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Cellular response to starvation	1
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	4
cytoplasm	4
translation	3
cellular response to stress	3
cellular anatomical structure	3
cellular response to chemical stress	2
response to endoplasmic reticulum stress	2
regulation of translation in response to stress	2
integrated stress response signaling	2
binding	2
intracellular membrane-bounded organelle	2
autophagy of mitochondrion	1
macroautophagy	1
formation of translation initiation ternary complex	1
metabolic process	1
response to stress	1
negative regulation of translational initiation	1
membraneless organelle assembly	1
cellular response to starvation	1
response to amino acid starvation	1
response to oxidative stress	1
response to heat	1
response to UV	1
cellular response to light stimulus	1
ER-nucleus signaling pathway	1
endoplasmic reticulum unfolded protein response	1
regulation of translational initiation	1
response to amino acid	1
response to nitrogen compound	1
response to oxygen-containing compound	1
cellular response to manganese ion	1
type B pancreatic cell apoptotic process	1
positive regulation of epithelial cell apoptotic process	1
regulation of type B pancreatic cell apoptotic process	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1

Protein interactions and networks

STRING

4574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2S1	EIF2S3	P41091	998
EIF2S1	EIF2S2	P20042	998
EIF2S1	EIF2AK2	P19525	990
EIF2S1	EIF2AK3	Q9NZJ5	974
EIF2S1	EIF2AK4	Q9P2K8	974
EIF2S1	EIF3B	P55884	937
EIF2S1	HSPA5	P11021	936
EIF2S1	EIF1	P41567	935
EIF2S1	PPP1R15A	O75807	923
EIF2S1	ATF6	P18850	923
EIF2S1	EIF2AK1	Q9BQI3	903
EIF2S1	DDIT3	P35638	902
EIF2S1	ATF4	P18848	899
EIF2S1	ERN1	O75460	895
EIF2S1	PPP1R15B	Q5SWA1	874

IntAct

202 interactions, top by confidence:

A	B	Type	Score
EIF2S3	EIF2S1	psi-mi:“MI:0407”(direct interaction)	0.820
PPP1CA	PPP1R15A	psi-mi:“MI:0403”(colocalization)	0.820
EIF2S1	EIF2S3	psi-mi:“MI:0914”(association)	0.820
EIF2S1	EIF2S2	psi-mi:“MI:0407”(direct interaction)	0.810
EIF2S2	EIF2S1	psi-mi:“MI:0407”(direct interaction)	0.810
EIF2S2	EIF2S1	psi-mi:“MI:0914”(association)	0.810
EIF2S1	EIF2S2	psi-mi:“MI:0914”(association)	0.810
EIF2S1	EIF2S2	psi-mi:“MI:0403”(colocalization)	0.810
EIF2S1	EIF2AK2	psi-mi:“MI:0407”(direct interaction)	0.780
EIF2AK2	EIF2S1	psi-mi:“MI:0217”(phosphorylation reaction)	0.780
EIF2AK2	EIF2S1	psi-mi:“MI:0915”(physical association)	0.780
EIF2S2	CDC123	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EIF2S1	PRMT7	psi-mi:“MI:0915”(physical association)	0.670
Eif2ak3	EIF2S1	psi-mi:“MI:0407”(direct interaction)	0.650
EIF2S1	Eif2ak3	psi-mi:“MI:0407”(direct interaction)	0.650
DDX3X	EIF2S1	psi-mi:“MI:0914”(association)	0.640
DDX3X	EIF2S1	psi-mi:“MI:0403”(colocalization)	0.640
EIF2S1	DDX3X	psi-mi:“MI:0407”(direct interaction)	0.640
PPP1R15A	EIF2S1	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (410): EIF2S1 (Affinity Capture-MS), EIF2S1 (Affinity Capture-MS), EIF2S1 (Affinity Capture-MS), EIF2S1 (Affinity Capture-MS), EIF2S1 (Biochemical Activity), EIF2S1 (Biochemical Activity), EIF2S1 (Affinity Capture-MS), EIF2S1 (Two-hybrid), EIF2S1 (Co-fractionation), EIF2S1 (Co-fractionation), EIF2S1 (Co-fractionation), EIF2S1 (Co-fractionation), EIF2S1 (Co-fractionation), EIF2S1 (Co-fractionation), EIF2S1 (Co-fractionation)

ESM2 similar proteins: A0A509AJP9, A3GHT9, A5DK38, A5DWY7, A7A0X4, A7A1H2, A7TFN8, A7TPD4, B0G189, B3LT39, B3RHG9, B5VN01, B6K286, B9W9T4, B9WBR8, C4YIT6, C8ZDQ3, D2VRR7, O13914, O94316, P05198, P06786, P20459, P20460, P25039, P33309, P41001, P41374, P41810, P46943, P68101, P68102, Q09704, Q5CD97, Q5R493, Q5ZLX2, Q6BPD3, Q6CRY5, Q6FR62, Q6FUQ6

Diamond homologs: A0A509AJP9, A0LHM4, A4VPN6, A4XYD6, A5FQT2, A5W983, A6VCJ6, A6VU33, A8AV53, A8EU19, A9B8G1, A9WEJ7, B0KHX3, B1IAA9, B1J2B3, B2A3A3, B2IMQ9, B5E2A0, B7V1F2, B8DFZ6, B8G3Z1, B8ZMC0, B9LH03, B9MR54, C1C5V9, C1CCW4, C1CQ76, C1DFK5, C1L2N7, C3K255, O87792, P05198, P20459, P20460, P41374, P56286, P68101, P68102, P83268, Q02FT2

SIGNOR signaling

30 interactions.

A	Effect	B	Mechanism
EIF2AK2	down-regulates	EIF2S1	phosphorylation
EIF2AK3	down-regulates	EIF2S1	phosphorylation
EIF2AK1	up-regulates	EIF2S1	phosphorylation
EIF2AK1	down-regulates	EIF2S1	phosphorylation
EIF2AK3	“down-regulates activity”	EIF2S1	phosphorylation
EIF2AK4	“down-regulates activity”	EIF2S1	phosphorylation
EIF2AK1	“down-regulates activity”	EIF2S1	phosphorylation
EIF2S1	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
EIF2S1	“up-regulates quantity by expression”	HBG1	“transcriptional regulation”
EIF2S1	“up-regulates quantity by expression”	ATF4	“transcriptional regulation”
PPP1CC	“up-regulates activity”	EIF2S1	dephosphorylation
EIF2S1	up-regulates	Protein_synthesis
EIF2AK2	“down-regulates activity”	EIF2S1	phosphorylation
EIF2S1	“down-regulates quantity”	ATF4	“transcriptional regulation”
BZW2	“up-regulates activity”	EIF2S1	binding
EIF2S1	“form complex”	Ternary_GTP_eIF2_tRNA_complex	binding
EIF2B5	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B1	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B2	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B3	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
EIF2B4	“up-regulates activity”	EIF2S1	“guanine nucleotide exchange factor”
SYVN1	“down-regulates quantity by destabilization”	EIF2S1	ubiquitination
CELF1	“up-regulates activity”	EIF2S1	binding
PRKCD	unknown	EIF2S1	phosphorylation
THAP12	unknown	EIF2S1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 190 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
Ribosomal scanning and start codon recognition	10	13.9×	2e-06
Dengue Virus Genome Translation and Replication	6	13.9×	6e-04
Formation of the ternary complex, and subsequently, the 43S complex	8	12.6×	3e-05
Translation initiation complex formation	9	12.5×	1e-05
GTP hydrolysis and joining of the 60S ribosomal subunit	12	8.8×	5e-06
L13a-mediated translational silencing of Ceruloplasmin expression	11	8.1×	2e-05
Formation of a pool of free 40S subunits	8	6.5×	3e-03
SRP-dependent cotranslational protein targeting to membrane	8	5.8×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	33.6×	5e-05
regulation of translational initiation	9	25.2×	4e-08
translational initiation	11	23.6×	1e-09
positive regulation of MAP kinase activity	5	19.4×	5e-04
peptidyl-tyrosine phosphorylation	6	15.1×	3e-04
cell surface receptor protein tyrosine kinase signaling pathway	12	12.5×	1e-07
negative regulation of translation	9	10.6×	4e-05
cytoplasmic translation	9	10.0×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1164 predictions. Top by Δscore:

Variant	Effect	Δscore
14:67365007:AG:A	donor_gain	1.0000
14:67365008:GG:G	donor_gain	1.0000
14:67365009:G:GA	donor_loss	1.0000
14:67365009:G:GG	donor_gain	1.0000
14:67374545:ACT:A	donor_gain	1.0000
14:67374548:G:GG	donor_gain	1.0000
14:67376436:TA:T	acceptor_loss	1.0000
14:67376438:GGTTT:G	acceptor_gain	1.0000
14:67376571:GCATT:G	donor_gain	1.0000
14:67376575:T:G	donor_gain	1.0000
14:67376586:GTCTC:G	donor_gain	1.0000
14:67376591:G:GG	donor_gain	1.0000
14:67380646:T:G	acceptor_gain	1.0000
14:67380646:T:TA	acceptor_gain	1.0000
14:67380652:T:TA	acceptor_gain	1.0000
14:67380761:AGCAG:A	donor_loss	1.0000
14:67380762:GCAG:G	donor_gain	1.0000
14:67380762:GCAGG:G	donor_loss	1.0000
14:67380763:CAG:C	donor_loss	1.0000
14:67380764:AGG:A	donor_loss	1.0000
14:67380765:GGTA:G	donor_loss	1.0000
14:67380766:G:C	donor_loss	1.0000
14:67380767:T:G	donor_loss	1.0000
14:67381587:TTGTA:T	acceptor_loss	1.0000
14:67381590:TA:T	acceptor_loss	1.0000
14:67381591:A:AG	acceptor_gain	1.0000
14:67381591:AGAT:A	acceptor_loss	1.0000
14:67381592:G:A	acceptor_loss	1.0000
14:67381592:G:GG	acceptor_gain	1.0000
14:67381592:GA:G	acceptor_gain	1.0000

AlphaMissense

2094 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:67364807:C:A	P14T	1.000
14:67364807:C:T	P14S	1.000
14:67364808:C:A	P14H	1.000
14:67364838:T:A	V24D	1.000
14:67364858:G:A	G31R	1.000
14:67364858:G:C	G31R	1.000
14:67364858:G:T	G31W	1.000
14:67364859:G:A	G31E	1.000
14:67364859:G:T	G31V	1.000
14:67364862:C:A	A32D	1.000
14:67364868:T:A	V34D	1.000
14:67364874:T:C	L36S	1.000
14:67364874:T:G	L36W	1.000
14:67364897:G:C	G44R	1.000
14:67364897:G:T	G44C	1.000
14:67364898:G:A	G44D	1.000
14:67364898:G:T	G44V	1.000
14:67364901:T:C	M45T	1.000
14:67364902:G:A	M45I	1.000
14:67364902:G:C	M45I	1.000
14:67364902:G:T	M45I	1.000
14:67364904:T:A	I46N	1.000
14:67364904:T:C	I46T	1.000
14:67364912:A:C	S49R	1.000
14:67364913:G:T	S49I	1.000
14:67364914:T:A	S49R	1.000
14:67364914:T:G	S49R	1.000
14:67364915:G:A	E50K	1.000
14:67364916:A:C	E50A	1.000
14:67364916:A:G	E50G	1.000

dbSNP variants (sampled 300 via entrez): RS1000004027 (14:67372494 A>G), RS1000043200 (14:67370231 G>A), RS1000102764 (14:67367338 C>G,T), RS1000249789 (14:67363862 G>A), RS1000284590 (14:67376946 A>G), RS1000311255 (14:67386532 T>A), RS1000405831 (14:67386215 A>G), RS1000519060 (14:67359244 G>A), RS1000563996 (14:67379394 A>G), RS1000571710 (14:67359522 G>C), RS1000992207 (14:67365866 T>C), RS1001040761 (14:67384481 A>G), RS1001214927 (14:67365922 G>A), RS1001361369 (14:67371431 A>AG), RS1001478524 (14:67378348 G>A,T)

Disease associations

OMIM: gene MIM:603907 | disease phenotypes: MIM:248800, MIM:619687

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	Autosomal recessive

Mondo (3): Marinesco-Sjogren syndrome (MONDO:0009567), dystonia 33 (MONDO:0030513), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Marinesco-Sjögren syndrome (Orphanet:559)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_673	Metabolite levels	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009770	leucine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1255131 (SINGLE PROTEIN)

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

ChEMBL bioactivities

30 potent at pChembl≥5 of 30 total, top 30 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	IC50	9	nM	CHEMBL4857782
7.75	IC50	18	nM	CHEMBL4858308
7.64	IC50	23	nM	CHEMBL4848143
7.57	IC50	27	nM	CHEMBL4869882
7.48	IC50	33	nM	CHEMBL4862478
7.40	IC50	40	nM	CHEMBL4853221
7.40	IC50	40	nM	CHEMBL4848359
7.38	IC50	42	nM	CHEMBL4861671
7.35	IC50	45	nM	CHEMBL4863698
7.31	IC50	49	nM	CHEMBL4870100
7.27	IC50	54	nM	CHEMBL4870780
7.24	IC50	58	nM	CHEMBL4875875
7.14	IC50	72	nM	CHEMBL4851480
7.11	Kd	77.87	nM	CHEMBL5653589
7.11	ED50	77.87	nM	CHEMBL5653589
6.94	IC50	114	nM	CHEMBL4876496
6.74	IC50	181	nM	CHEMBL4854504
6.73	IC50	187	nM	CHEMBL4852735
6.70	IC50	198	nM	CHEMBL4870495
6.51	IC50	307	nM	CHEMBL4866245
6.50	IC50	313	nM	CHEMBL4846663
6.44	IC50	366	nM	CHEMBL4870565
6.20	IC50	638	nM	CHEMBL4849149
5.67	IC50	2130	nM	CHEMBL4868021
5.65	IC50	2220	nM	CHEMBL4876223
5.63	IC50	2360	nM	CHEMBL4853233
5.52	IC50	3020	nM	CHEMBL4848921
5.48	IC50	3340	nM	CHEMBL4854364
5.39	IC50	4030	nM	CHEMBL4858598
5.12	IC50	7650	nM	CHEMBL4878188

PubChem BioAssay actives

29 with measured affinity, of 145 total; 29 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
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-ethylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0090	uM
2-amino-5-[4-[[(2R)-2-(3-ethylphenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0180	uM
2-amino-5-[2-chloro-4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]phenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0230	uM
2-amino-N-cyclopropyl-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]pyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0270	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0330	uM
3-amino-6-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-methylpyrazine-2-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0400	uM
2-amino-5-[4-[[(2R)-2-(3-chlorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0400	uM
3-amino-6-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyrazine-2-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0420	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-ethylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0450	uM
propan-2-yl 2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]pyridine-3-carboxylate	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0490	uM
2-amino-5-[4-[[(2R)-2-hydroxy-2-(3-methylphenyl)acetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0540	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-methylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0580	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-fluorophenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0720	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148301: Binding affinity to human EIF2S1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0779	uM
2-amino-N-tert-butyl-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]pyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.1140	uM
5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.1810	uM
2-amino-5-[4-[[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.1870	uM
2-amino-5-[4-[[(2R)-2-hydroxy-2-phenylacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.1980	uM
2-amino-5-[2-methyl-4-[(2-phenylacetyl)amino]phenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.3070	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]phenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.3130	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methoxyphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.3660	uM
5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-2-methyl-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.6380	uM
2-amino-5-[4-[[(2R)-2-hydroxy-2-phenylpropanoyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	2.1300	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N,N-dimethylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	2.2200	uM
2-amino-5-[2-methyl-4-(phenylcarbamoylamino)phenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	2.3600	uM
2-amino-5-[4-[[(2S)-2-hydroxy-2-phenylpropanoyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	3.0200	uM
2-amino-5-[4-[[(2R)-2-methoxy-2-phenylacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	3.3400	uM
5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-2-(methylamino)-N-propan-2-ylpyridine-3-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	4.0300	uM
3-amino-6-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridazine-4-carboxamide	1763228: Inhibition of eIF2alpha (unknown origin) assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	7.6500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tunicamycin	decreases reaction, increases phosphorylation, increases expression, affects reaction, decreases expression	13
Thapsigargin	increases phosphorylation, increases expression, decreases reaction	12
arsenite	increases reaction, decreases expression, affects reaction, decreases reaction, affects cotreatment (+2 more)	9
sodium arsenite	decreases reaction, increases phosphorylation, affects binding, increases reaction, decreases expression (+1 more)	9
4-phenylbutyric acid	increases phosphorylation, decreases expression, decreases reaction, increases expression	8
salubrinal	increases reaction, affects cotreatment, increases phosphorylation, decreases activity, decreases response to substance (+2 more)	7
Acetylcysteine	increases phosphorylation, decreases reaction	6
bisphenol A	decreases reaction, increases phosphorylation, affects cotreatment, decreases expression	5
Cadmium Chloride	increases abundance, increases expression, increases phosphorylation, increases reaction	5
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases phosphorylation, increases expression, affects reaction, affects cotreatment	4
Resveratrol	affects cotreatment, increases expression, decreases reaction, increases phosphorylation	4
Arsenic Trioxide	affects reaction, decreases reaction, increases phosphorylation, affects binding, increases reaction (+1 more)	4
Rotenone	decreases reaction, increases expression, affects reaction, increases phosphorylation	4
Tobacco Smoke Pollution	decreases reaction, increases phosphorylation, increases expression, affects expression, affects cotreatment	4
Valproic Acid	affects cotreatment, increases expression, affects expression	4
Bortezomib	affects reaction, increases phosphorylation, decreases reaction	3
Estradiol	affects binding, increases reaction, increases expression	3
Palmitates	decreases reaction, increases phosphorylation	3
aristolochic acid I	increases phosphorylation, increases expression	2
GSK2656157	increases phosphorylation, decreases reaction	2
bisphenol F	increases expression, increases phosphorylation	2
triphenyl phosphate	affects cotreatment, affects phosphorylation, affects expression	2
sulforaphane	increases phosphorylation, increases expression, increases reaction, decreases reaction	2
ochratoxin A	increases phosphorylation, decreases reaction	2
hydroquinone	increases phosphorylation, decreases reaction	2
boric acid	increases phosphorylation	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
dorsomorphin	affects cotreatment, increases expression, increases phosphorylation	2
7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine	increases expression, decreases expression, decreases phosphorylation, decreases reaction, increases phosphorylation	2
Ursolic Acid	decreases reaction, increases phosphorylation	2

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1261569	Binding	Inhibition of eIF2alpha autophosphorylation in human MCF7 cells	Synthesis and antitumor effect in vitro and in vivo of substituted 1,3-dihydroindole-2-ones. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02887365	PHASE4	UNKNOWN	A Phase II Study of Tegafur-Uracil as Maintenance Chemotherapy in Patients With Stage II of Colon Cancer
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT07549399	PHASE3	NOT_YET_RECRUITING	SCRT + Chemo Targeted Immuno-neoadjuvant Therapy for High-risk pMMR/MSS RC
NCT07551479	PHASE3	NOT_YET_RECRUITING	SCRT Based iTNT vs. LCRT Based TNT for MSS Locally Advanced Rectal Cancer
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT03271047	PHASE2	COMPLETED	Study of Binimetinib + Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation
NCT04030260	PHASE2	UNKNOWN	Regorafenib and PD-1 Antibody in Combination With Radiotherapy for pMMR/MSS Metastatic Colorectal Cancer
NCT04098068	PHASE2	COMPLETED	Study of MK-3475 (Pembrolizumab) in Patients With Microsatellite Unstable (MSI) Tumors (Cohort D)
NCT04483219	PHASE2	UNKNOWN	Tyrosine Kinase Inhibitor (TKI) + Anti-PD-1 Antibody in TKI-responded Microsatellite Stability/Proficient Mismatch Repair (MSS/pMMR) Metastatic Colorectal Adenocarcinoma.
NCT04527068	PHASE2	UNKNOWN	QL1101 in Combination With JS001 in Patients With pMMR/MSS Refractory Metastatic Colorectal Cancer
NCT04659382	PHASE2	UNKNOWN	Study to Evaluate Efficacy and Safety of Selective Internal Radiation Therapy Plus Xelox, Bevacizumab and Atezolizumab (Immune Chekpoint Inhibitor) in Patients With Liver-dominant Metastatic Colorectal Cancer
NCT05731726	PHASE2	RECRUITING	Serplulimab Combined With CAPEOX + Celecoxib as Neoadjuvant Treatment for Locally Advanced Rectal Cancer
NCT05733611	PHASE2	TERMINATED	RP2/RP3 in Combination With Atezolizumab and Bevacizumab for the Treatment of Patients With CRC
NCT05815303	PHASE2	UNKNOWN	XELOX Combined With Cadonilimab Versus XELOX as Neoadjuvant Treatment for Locally Advanced, pMMR Rectal Cancer
NCT05933980	PHASE2	UNKNOWN	Toripalimab,Celecoxib and Regorafenib in the Treatment of Refractory Advanced Colorectal Cancer
NCT05970302	PHASE2	RECRUITING	XELOX +Bev +Tislelizumab for First-line Treatment of MSS/pMMR RAS-mutated mCRC
NCT06321081	PHASE2	RECRUITING	ICE Study: Combination of Irinotecan Plus Cetuximab and Envafolimab as a Rechallenge Regimen in mCRC
NCT06415851	PHASE2	NOT_YET_RECRUITING	Chemotherapy Plus Bevacizumab and Anti-PD-1 Followed by Induction Therapy of Chemotherapy Plus Bevacizumab
NCT06593548	PHASE2	NOT_YET_RECRUITING	Lvosidenib (AK112) Combined With CapeOX and Radiotherapy in Patients With Unresectable Metastatic MSS-type Colorectal Cancer
NCT06850103	PHASE2	RECRUITING	SCRT-CAPEOX-Serplulimab for MSS/pMMR Rectal Cancer With Oligometastases
NCT06908031	PHASE2	RECRUITING	SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy for HIgh-Risk pMMR/MSS Rectal Cancer
NCT07156682	PHASE2	NOT_YET_RECRUITING	QL1706 Plus XELOX as Neoadjuvant Therapy for MSS/pMMR Clinical Stage III Colon Cancer
NCT07506109	PHASE2	RECRUITING	A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer
NCT07527520	PHASE2	NOT_YET_RECRUITING	Neoadjuvant Moderately Hypofractionated Radiotherapy Combined With Chemotherapy and Immunotherapy for High-risk pMMR/MSS Locally Advanced Rectal Cancer: A Prospective, Multi-center Randomized Control Phase II Trial
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03274804	PHASE1	COMPLETED	Combined PD-1 and CCR5 Inhibition for the Treatment of Refractory Microsatellite Stable mCRC
NCT04046445	PHASE1	ACTIVE_NOT_RECRUITING	Phase 1b Study to Evaluate ATP128, VSV-GP128 and BI 754091, in Patients With Stage IV Colorectal Cancer
NCT07001592	PHASE1	RECRUITING	Intra-tumoral (IT) Injection of vvDD-hIL2-2-RG-1 for Metastatic Gastrointestinal and Peritoneal Tumors
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy