ATF4

Summary

ATF4 (activating transcription factor 4, HGNC:786) is a protein-coding gene on chromosome 22q13.1, encoding Cyclic AMP-dependent transcription factor ATF-4 (P18848). Transcription factor that binds the cAMP response element (CRE) (consensus: 5’-GTGACGT[AC][AG]-3’) and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress r…. It is a selective cancer dependency (DepMap: 71.8% of cell lines).

This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein-protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication.

Source: NCBI Gene 468 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 91 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 71.8% of screened cell lines
• Transcription factor: yes — 134 downstream targets (CollecTRI)
• MANE Select transcript: NM_182810

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:786
Approved symbol	ATF4
Name	activating transcription factor 4
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	TAXREB67, CREB-2
Ensembl gene	ENSG00000128272
Ensembl biotype	protein_coding
OMIM	604064
Entrez	468

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 20 protein_coding

ENST00000337304, ENST00000396680, ENST00000404241, ENST00000674568, ENST00000674835, ENST00000674920, ENST00000675582, ENST00000676346, ENST00000679776, ENST00000680446, ENST00000680748, ENST00000921524, ENST00000921525, ENST00000921526, ENST00000921527, ENST00000921528, ENST00000921529, ENST00000960424, ENST00000960425, ENST00000960426

RefSeq mRNA: 2 — MANE Select: NM_182810 NM_001675, NM_182810

CCDS: CCDS13996

Canonical transcript exons

ENST00000674920 — 3 exons

Exon	Start	End
ENSE00001525916	39521354	39521671
ENSE00003903073	39520562	39520751
ENSE00004282355	39521773	39522683

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 348.9000 / max 1896.0692, expressed in 1827 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192366	347.5852	1827
192364	0.3807	152
192365	0.3570	156
192368	0.3274	156
192367	0.2497	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	99.62	gold quality
lower esophagus	UBERON:0013473	99.59	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.59	gold quality
popliteal artery	UBERON:0002250	99.55	gold quality
tibial artery	UBERON:0007610	99.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.55	gold quality
body of stomach	UBERON:0001161	99.52	gold quality
fundus of stomach	UBERON:0001160	99.51	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.51	gold quality
adipose tissue	UBERON:0001013	99.50	gold quality
right coronary artery	UBERON:0001625	99.50	gold quality
omental fat pad	UBERON:0010414	99.49	gold quality
body of pancreas	UBERON:0001150	99.48	gold quality
left coronary artery	UBERON:0001626	99.48	gold quality
descending thoracic aorta	UBERON:0002345	99.47	gold quality
ventricular zone	UBERON:0003053	99.45	gold quality
ascending aorta	UBERON:0001496	99.44	gold quality
thoracic aorta	UBERON:0001515	99.44	gold quality
prostate gland	UBERON:0002367	99.44	gold quality
mucosa of stomach	UBERON:0001199	99.43	gold quality
body of uterus	UBERON:0009853	99.43	gold quality
tibial nerve	UBERON:0001323	99.42	gold quality
stomach	UBERON:0000945	99.41	gold quality
myometrium	UBERON:0001296	99.41	gold quality
gastrocnemius	UBERON:0001388	99.41	gold quality
upper lobe of left lung	UBERON:0008952	99.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.40	gold quality
pancreas	UBERON:0001264	99.39	gold quality
muscle of leg	UBERON:0001383	99.38	gold quality
colon	UBERON:0001155	99.37	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	143.78
E-CURD-46	yes	35.77
E-GEOD-135922	yes	9.57
E-GEOD-93593	yes	9.19
E-MTAB-8894	no	620.59
E-GEOD-124858	no	370.80
E-MTAB-7316	no	35.11
E-MTAB-10137	no	5.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

134 targets.

Target	Regulation
AARS2	Activation
ACOT11
ADAM2
APOE	Activation
ASNS	Activation
ATF2
ATF3	Activation
ATF4
ATF5	Unknown
ATF6
ATG5	Activation
BBC3	Unknown
BGLAP	Unknown
CA9	Unknown
CARS1	Activation
CARS2	Activation
CASP12
CCL2	Unknown
CCNA2
CCND1	Activation
CDC42
CEBPA
CEBPB	Activation
CEBPE
CEL
CHAC1	Activation
CNTN2
CREB1	Repression
CREBBP
CSF1R

JASPAR motifs

Motif	Name	Family
MA0833.1	ATF4	ATF-4-related factors
MA0833.2	ATF4	ATF-4-related factors
MA0833.3	ATF4	ATF-4-related factors

JASPAR matrix evidence (PMIDs): PMID:2516827, PMID:22819556

Upstream regulators (CollecTRI, top): ATF2, ATF3, ATF4, BZW2, CEBPB, CEBPE, CLOCK, CREB1, DDIT3, EIF2AK3, EIF2S1, ESR1, HDAC4, IRF7, MYC, NFE2L2, NUPR1, PIGBOS1, TRIB3, USF1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 71.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• mediator of the nutrient-sensing response pathway that activates the asparagine synthetase gene (PMID:11960987)
• interaction between RPB3 and ATF4 (PMID:12860379)
• ATF4 and ATF2 have roles in regulating CHOP expression (PMID:14630918)
• Expression of ATF4 was found to correlate with cisplatin sensitivity in human cancer cell lines. (PMID:14695168)
• ATF4 has a role in regulating VEGF expression (PMID:14747470)
• Data demonstrate the essential role of activating transcription factor 4 (ATF4) in the response to hypoxic stress, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2alpha-mediated inhibition of translation. (PMID:15314157)
• ATF3-FL and C/EBPbeta act as transcriptional suppressors for the ASNS gene to counterbalance the transcription rate activated by ATF4 following amino acid deprivation (PMID:15385533)
• Results suggest that mitosin is a negative regulator of ATF4 in interphase through direct interaction. (PMID:15677469)
• both p300 and CBP increase ATF4 transcriptional activity (PMID:16219772)
• activation by nephrocystin-6 in Joubert syndrome (PMID:16682973)
• Endoplasmic reticulum stress induction of IGFBP-1 involves ATF4 (PMID:16687408)
• Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any. (PMID:17346882)
• ATF4 may regulate myeloid gene expression differentially by potentiating C/EBPepsilon but inhibiting C/EBPalpha-mediated transcriptional activation. (PMID:17347301)
• TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. (PMID:17369260)
• PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems. (PMID:17684156)
• The results indicate that TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. (PMID:17707795)
• overexpression of either CREB or ATF4 enhanced the activation of the HEC1 promoter and overexpression of both of them had an additive effect on the activation of the HEC1 transcription. (PMID:17822787)
• The ATF4-mediated up-regulation of Ape1 and other genes plays a key role against arsenite-mediated toxicity and mutagenesis. (PMID:17938202)
• 23P-ATF4 peptide fits the binding pocket of protein beta-TrCP very well, considering that the DpSGIXXpSXE motif adopts an S-turning conformation contrary to the extended DpSGXXpS motif in the other known beta-TrCP ligands. (PMID:17996332)
• ATF4 gene may be involved in susceptibility to schizophrenia with sex-dependent effect. (PMID:18163433)
• TFIIA gamma together with ATF4 and Runx2 stimulates osteocalcin promoter activity and endogenous mRNA expression. (PMID:18171674)
• 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)
• Multiple pathways are involved in the anoxia response of SKIP3 including HuR-regulated RNA stability, NF-kappaB and ATF4 (PMID:18408768)
• characterize unfolded protein response ATF4 branch as an important mechanism mediating up-regulation of VEGF by OxPLs (PMID:18451308)
• Compared with COPD and donor lungs, protein levels of ER stress mediators, such as ATF-6 and ATF-4 and the apoptosis-inductor CHOP as well as XBP-1, were significantly elevated in lung homogenates and AECIIs of IPF lungs (PMID:18635891)
• Despite increased ATF4 binding at the C/EBP-ATF composite site following activation of the unfolded protein response, system A transporter 2 (SNAT2) transcription activity is repressed (PMID:18697751)
• CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF4-containing genes, such as ASNS (PMID:18940792)
• ATF4 and phospho-eIF2alpha levels are tightly correlated and up-regulated in Alzheimer disease (PMID:19017641)
• celecoxib up-regulates the expression of S100P through an ATF4-mediated endoplasmic reticulum stress response (PMID:19073601)
• The results suggest that REDD1 expression is upregulated during ER stress through a mechanism involving activation of PERK, phosphorylation of eIF2alpha, and increased ATF4 expression. (PMID:19114033)
• In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4). (PMID:19193809)
• Induction of autophagy through ATF4 may be an important resistance mechanism to Bortezomib treatment in breast cancer, and targeting autophagy may represent a novel approach to sensitize breast cancers to Bortezomib. (PMID:19417138)
• ATF4 alone is sufficient to trigger an amino acid-responsive transcriptional control program (PMID:19509279)
• TRIF-mediated signals from toll-like receptors selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. (PMID:19855386)
• Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4 (PMID:19946894)
• ATF4 mediates ER stress-induced cell death of neuroectodermal tumor cells in response to fenretinide or bortezomib (PMID:20022965)
• Oxidized phospholipids induce an angiogenic switch in endothelial cells at least partially acting via a cross-talk between NRF2 and ATF4, thus leading to induction of VEGF. (PMID:20185790)
• 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)
• ATF4 has a key role in the regulation of autophagy in response to ER stress and is a direct link between endoplasmic stress response and autophagic machinery. (PMID:20514020)
• 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)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atf4b	ENSDARG00000038141
danio_rerio	atf4a	ENSDARG00000111939
mus_musculus	Atf4	ENSMUSG00000042406
rattus_norvegicus	Atf4	ENSRNOG00000017801
caenorhabditis_elegans		WBGENE00000221
caenorhabditis_elegans		WBGENE00013878

Paralogs (1): ATF5 (ENSG00000169136)

Protein

Protein identifiers

Cyclic AMP-dependent transcription factor ATF-4 — P18848 (reviewed: P18848)

Alternative names: Activating transcription factor 4, Cyclic AMP-responsive element-binding protein 2, Tax-responsive enhancer element-binding protein 67

All UniProt accessions (7): P18848, A0A6Q8PFH6, A0A6Q8PG17, A0A6Q8PGY1, A0A6Q8PHB3, A0A7P0Z4J5, B4DJD4

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds the cAMP response element (CRE) (consensus: 5’-GTGACGT[AC][AG]-3’) and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR). Binds to asymmetric CRE’s as a heterodimer and to palindromic CRE’s as a homodimer. Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress. During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery. Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation. Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress. Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress. However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation. Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved. Activates the expression of COX7A2L/SCAF1 downstream of the EIF2AK3/PERK-mediated unfolded protein response, thereby promoting formation of respiratory chain supercomplexes and increasing mitochondrial oxidative phosphorylation. Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress. May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress. In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity. Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory. Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding. (Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I.

Subunit / interactions. Binds DNA as a homodimer and as a heterodimer. Heterodimer; heterodimerizes with CEBPB. Heterodimer; heterodimerizes with DDIT3/CHOP. Interacts with CEP290 (via an N-terminal region). Interacts with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3. Interacts (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini). Forms a heterodimer with TXLNG in osteoblasts. Interacts (via its DNA binding domain) with FOXO1 (C-terminal half); the interaction occurs in osteoblasts and regulates glucose homeostasis through suppression of beta-cell proliferation and a decrease in insulin production. Interacts with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors. Interacts with ABRAXAS2. Interacts with TRIB3, inhibiting the transactivation activity of ATF4. Interacts with DISC1; which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding. Interacts with EP300/p300; EP300/p300 stabilizes ATF4 and increases its transcriptional activity independently of its catalytic activity by preventing its ubiquitination.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm. Cell membrane. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4. Interaction with EP300/p300 inhibits ubiquitination by SCF(BTRC). Phosphorylation at Ser-245 by RPS6KA3/RSK2 in osteoblasts enhances transactivation activity and promotes osteoblast differentiation. Phosphorylated on the betaTrCP degron motif at Ser-219, followed by phosphorylation at Thr-213, Ser-224, Ser-231, Ser-235 and Ser-248, promoting interaction with BTRC and ubiquitination. Phosphorylation is promoted by mTORC1. Phosphorylation at Ser-215 by CK2 decreases its stability. Phosphorylated by NEK6. Hydroxylated by PHD3, leading to decreased protein stability.

Domain organisation. The BetaTrCP degron motif promotes binding to BTRC when phosphorylated.

Induction. Regulated at the translational level in response to various stress such as endoplasmic reticulum stress, amino acid starvation or oxidative stress. In the absence of stress, ribosomes re-initiate translation at an inhibitory open reading frame (uORF) upstream of the ATF4 transcript, which precludes AFT4 translation. In response to stress and subsequent EIF2S1/eIF-2-alpha phosphorylation, ribosomes bypass the inhibitory uORF and re-initiate translation at the AFT4 coding sequence.

Similarity. Belongs to the bZIP family.

RefSeq proteins (2): NP_001666, NP_877962* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF00170

UniProt features (41 total): modified residue 10, mutagenesis site 10, cross-link 4, region of interest 4, sequence conflict 4, sequence variant 3, chain 1, domain 1, helix 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9TFU	X-RAY DIFFRACTION	2
1CI6	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18848-F1	62.95	0.20

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 (14): 215, 219, 224, 231, 235, 236, 245, 248, 311, 53, 259, 267, 272, 213

Mutagenesis-validated functional residues (10):

Position	Phenotype
156	increased stability in low oxygen conditions; when associated with a-162, a-164, a-167 and a-174.
162	increased stability in low oxygen conditions; when associated with a-156, a-164, a-167 and a-174.
164	increased stability in low oxygen conditions; when associated with a-156, a-162, a-167 and a-174.
167	increased stability in low oxygen conditions; when associated with a-156, a-162, a-164 and a-174.
174	increased stability in low oxygen conditions; when associated with a-156, a-162, a-164 and a-167.
213	does not affect phosphorylation by ck2.
215	abolished phosphorylation by ck2 leading to increased stability.
219	abolished phosphorylation on the betatrcp degron motif, interaction with btrc and subsequent ubiquitination.
245	abolished phosphorylation by rps6ka3/rsk2.
311	decreased acetylation without affecting ubiquitination by scf(btrc).

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress
R-HSA-381042	PERK regulates gene expression
R-HSA-381183	ATF6 (ATF6-alpha) activates chaperone genes
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency
R-HSA-9818027	NFE2L2 regulating anti-oxidant/detoxification enzymes
R-HSA-9818035	NFE2L2 regulating ER-stress associated genes
R-HSA-2262752	Cellular responses to stress
R-HSA-381033	ATF6 (ATF6-alpha) activates chaperones
R-HSA-381119	Unfolded Protein Response (UPR)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711097	Cellular response to starvation
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9759194	Nuclear events mediated by NFE2L2

MSigDB gene sets: 0 (showing top):

GO Biological Process (50): negative regulation of transcription by RNA polymerase II (GO:0000122), gluconeogenesis (GO:0006094), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), intracellular calcium ion homeostasis (GO:0006874), gamma-aminobutyric acid signaling pathway (GO:0007214), response to toxic substance (GO:0009636), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), neuron differentiation (GO:0030182), bone mineralization (GO:0030282), endoplasmic reticulum unfolded protein response (GO:0030968), response to nutrient levels (GO:0031667), negative regulation of translational initiation in response to stress (GO:0032057), circadian regulation of gene expression (GO:0032922), cellular response to amino acid starvation (GO:0034198), cellular response to oxidative stress (GO:0034599), cellular response to UV (GO:0034644), response to endoplasmic reticulum stress (GO:0034976), embryonic hemopoiesis (GO:0035162), PERK-mediated unfolded protein response (GO:0036499), cellular response to glucose starvation (GO:0042149), mRNA transcription by RNA polymerase II (GO:0042789), positive regulation of apoptotic process (GO:0043065), negative regulation of potassium ion transport (GO:0043267), positive regulation of neuron apoptotic process (GO:0043525), regulation of osteoblast differentiation (GO:0045667), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase I (GO:0045943), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of synaptic plasticity (GO:0048167), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), positive regulation of biomineral tissue development (GO:0070169), lens fiber cell morphogenesis (GO:0070309), obsolete L-asparagine metabolic process (GO:0070982), cellular response to hypoxia (GO:0071456), negative regulation of cold-induced thermogenesis (GO:0120163), integrated stress response signaling (GO:0140467), HRI-mediated signaling (GO:0140468)

GO Molecular Function (20): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), cAMP response element binding protein binding (GO:0008140), protein kinase binding (GO:0019901), cAMP response element binding (GO:0035497), identical protein binding (GO:0042802), leucine zipper domain binding (GO:0043522), sequence-specific DNA binding (GO:0043565), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), general transcription initiation factor binding (GO:0140296), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), protein binding (GO:0005515), DNA-binding transcription factor binding (GO:0140297)

GO Cellular Component (21): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), nuclear speck (GO:0016607), dendrite membrane (GO:0032590), protein-containing complex (GO:0032991), nuclear periphery (GO:0034399), neuron projection (GO:0043005), RNA polymerase II transcription regulator complex (GO:0090575), Lewy body core (GO:1990037), ATF4-CREB1 transcription factor complex (GO:1990589), ATF1-ATF4 transcription factor complex (GO:1990590), CHOP-ATF4 complex (GO:1990617), transcription regulator complex (GO:0005667), mitochondrion (GO:0005739), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Cellular responses to stress	4
Unfolded Protein Response (UPR)	2
Nuclear events mediated by NFE2L2	2
PERK regulates gene expression	1
ATF6 (ATF6-alpha) activates chaperones	1
Cellular response to starvation	1
Cellular responses to stimuli	1
Cellular response to chemical stress	1
KEAP1-NFE2L2 pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
regulation of gene expression	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
RNA polymerase II transcription regulator complex	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor binding	2
transcription factor binding	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
glucose metabolic process	1
hexose biosynthetic process	1
regulation of RNA biosynthetic process	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
cell-cell signaling	1
GABA receptor activity	1
response to chemical	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell differentiation	1
generation of neurons	1
ossification	1
biomineral tissue development	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
response to stimulus	1
translational initiation	1
response to stress	1
negative regulation of translational initiation	1
circadian rhythm	1

Protein interactions and networks

STRING

2428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATF4	ATF6	P18850	942
ATF4	EIF2AK3	Q9NZJ5	928
ATF4	DDIT3	P35638	925
ATF4	EIF2S1	P05198	899
ATF4	HSPA5	P11021	898
ATF4	XBP1	P17861	892
ATF4	TRIB3	Q96RU7	856
ATF4	NFE2L2	Q16236	845
ATF4	EIF2AK4	Q9P2K8	842
ATF4	RUNX2	Q13950	842
ATF4	ERN1	O75460	833
ATF4	ASNS	P08184	832
ATF4	TXLNG	Q9NUQ3	832
ATF4	JUN	P05412	785
ATF4	PPP1R15A	O75807	777

IntAct

322 interactions, top by confidence:

A	B	Type	Score
ATF4	BTRC	psi-mi:“MI:0915”(physical association)	0.950
BTRC	ATF4	psi-mi:“MI:0915”(physical association)	0.950
ATF4	TRIB3	psi-mi:“MI:0915”(physical association)	0.900
TRIB3	ATF4	psi-mi:“MI:0915”(physical association)	0.900
BFSP2	ATF4	psi-mi:“MI:0915”(physical association)	0.890
ATF4	BFSP2	psi-mi:“MI:0915”(physical association)	0.890

BioGRID (194): ATF4 (Two-hybrid), ATF4 (Affinity Capture-MS), EP300 (Affinity Capture-Western), CEBPG (Two-hybrid), GOLGA1 (Two-hybrid), GPS2 (Two-hybrid), BFSP2 (Two-hybrid), BTRC (Two-hybrid), NDC80 (Two-hybrid), LDOC1 (Two-hybrid), CCDC106 (Two-hybrid), TRIB3 (Two-hybrid), GCC1 (Two-hybrid), GOLGA8EP (Two-hybrid), GOLGA8F (Two-hybrid)

ESM2 similar proteins: A1L1F6, A5D7E9, B7ZS37, F1QDF8, O08750, O09105, O35261, O54968, P01105, P18848, P28290, P40649, P56931, P78312, Q06507, Q07279, Q08AD1, Q08D88, Q14209, Q14494, Q16236, Q16621, Q28EW4, Q32NH9, Q3KQW7, Q3ZCH6, Q5M7N6, Q5NUA6, Q5RA25, Q5W1J6, Q5ZL67, Q60795, Q61985, Q66IG8, Q6IMZ0, Q708W1, Q708W2, Q7YR76, Q8AYC2, Q8CDG5

Diamond homologs: O70191, P18848, Q06507, Q6NW59, Q6P788, Q9ES19, Q9Y2D1, Q3ZCH6, Q9GPH3, Q22156

SIGNOR signaling

48 interactions.

A	Effect	B	Mechanism
RPS6KA3	up-regulates	ATF4	phosphorylation
EIF2S1	“up-regulates quantity by expression”	ATF4	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	DDIT4	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	FGF19	“transcriptional regulation”
“ER stress”	up-regulates	ATF4
ROS	up-regulates	ATF4
ATF4	“up-regulates quantity by expression”	NUPR1	“transcriptional regulation”
NUPR1	“up-regulates quantity by expression”	ATF4	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	ASNS	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	FGF21	“transcriptional regulation”
ATF4	“down-regulates quantity by repression”	HSPA5	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	SIGMAR1	“transcriptional regulation”
ATF4	“down-regulates quantity by repression”	ASNS	“transcriptional regulation”
EIF2S1	“down-regulates quantity”	ATF4	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	DDIT3	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	PPP1R15A	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	“NLRP1 inflammasome”	“transcriptional regulation”
PIGBOS1	“down-regulates quantity by repression”	ATF4	“transcriptional regulation”
BZW2	“up-regulates quantity by expression”	ATF4	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	AARS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	AARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	CARS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	CARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	DARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	EPRS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	LARS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	LARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	NARS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	NARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	SARS1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Response of EIF2AK1 (HRI) to heme deficiency	5	119.0×	1e-07
Response of EIF2AK4 (GCN2) to amino acid deficiency	5	18.5×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	11	198.1×	3e-21
response to endoplasmic reticulum stress	6	25.7×	2e-05
transcription by RNA polymerase II	6	10.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	4
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

666 predictions. Top by Δscore:

Variant	Effect	Δscore
22:39521605:GC:G	donor_gain	1.0000
22:39521670:GG:G	donor_gain	1.0000
22:39521671:GG:G	donor_gain	1.0000
22:39521771:A:AG	acceptor_gain	1.0000
22:39521771:AGAG:A	acceptor_gain	1.0000
22:39521772:G:GA	acceptor_gain	1.0000
22:39521772:GA:G	acceptor_gain	1.0000
22:39521772:GAGG:G	acceptor_gain	1.0000
22:39520315:A:T	donor_gain	0.9900
22:39520339:GCCTA:G	donor_gain	0.9900
22:39520344:G:GG	donor_gain	0.9900
22:39520375:GCCA:G	donor_gain	0.9900
22:39520748:TGGC:T	donor_gain	0.9900
22:39520749:GGC:G	donor_gain	0.9900
22:39520749:GGCG:G	donor_gain	0.9900
22:39520750:GC:G	donor_gain	0.9900
22:39520750:GCG:G	donor_gain	0.9900
22:39520752:G:GG	donor_gain	0.9900
22:39521760:AAAT:A	acceptor_gain	0.9900
22:39521767:TTGCA:T	acceptor_loss	0.9900
22:39521769:GCA:G	acceptor_loss	0.9900
22:39521770:CA:C	acceptor_loss	0.9900
22:39521772:G:GC	acceptor_loss	0.9900
22:39521772:GAGGA:G	acceptor_gain	0.9900
22:39520349:GTA:G	donor_gain	0.9800
22:39520407:C:G	donor_gain	0.9800
22:39520738:GCT:G	donor_gain	0.9800
22:39521669:AGG:A	donor_gain	0.9800
22:39521670:GGG:G	donor_gain	0.9800
22:39521671:GGTG:G	donor_loss	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000100497 (22:39519789 A>G), RS1001072408 (22:39521307 C>A,G,T), RS1001545052 (22:39521413 G>A), RS1001677346 (22:39520065 C>A,T), RS1001737141 (22:39519994 T>C), RS1002146205 (22:39520884 C>G,T), RS1002475945 (22:39520696 C>G,T), RS1002567786 (22:39522221 A>G), RS1003246146 (22:39523167 G>A), RS1004982883 (22:39520019 T>G), RS1005988092 (22:39521879 C>G,T), RS1006288557 (22:39518801 G>C), RS1006300408 (22:39522436 A>G), RS1007406867 (22:39519753 G>A), RS1007769856 (22:39519498 G>A)

Disease associations

OMIM: gene MIM:604064 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001725_110	Inflammatory bowel disease	4.000000e-33
GCST009600_37	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	9.000000e-11
GCST90002392_225	Mean corpuscular volume	8.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067624 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 12 (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
CHEMBL5569312	EVETIFATOR	2	12

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

ChEMBL bioactivities

77 potent at pChembl≥5 of 77 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.40	IC50	0.4	nM	CHEMBL5575150
9.15	IC50	0.7	nM	CHEMBL5574671
9.15	IC50	0.7	nM	CHEMBL5594712
8.82	IC50	1.5	nM	CHEMBL5867340
8.80	IC50	1.6	nM	CHEMBL5955424
8.72	IC50	1.9	nM	CHEMBL5589825
8.71	IC50	1.93	nM	CHEMBL5761401
8.70	IC50	1.98	nM	CHEMBL6012605
8.64	IC50	2.3	nM	CHEMBL5566312
8.62	IC50	2.4	nM	CHEMBL5591151
8.60	IC50	2.5	nM	CHEMBL5573122
8.59	IC50	2.6	nM	CHEMBL5946942
8.57	IC50	2.7	nM	CHEMBL4303573
8.51	IC50	3.1	nM	CHEMBL5936933
8.47	IC50	3.36	nM	CHEMBL6040317
8.44	IC50	3.6	nM	CHEMBL5976800
8.44	IC50	3.6	nM	CHEMBL5934555
8.42	IC50	3.8	nM	CHEMBL5590478
8.38	IC50	4.16	nM	CHEMBL6012605
8.30	IC50	5	nM	CHEMBL5593424
8.28	IC50	5.3	nM	CHEMBL5572905
8.24	IC50	5.7	nM	CHEMBL5887716
8.22	IC50	6	nM	CHEMBL5572011
8.17	IC50	6.8	nM	CHEMBL5567438
8.09	IC50	8.1	nM	CHEMBL5565290
8.07	IC50	8.5	nM	CHEMBL5573131
8.03	IC50	9.4	nM	CHEMBL5571595
8.01	IC50	9.8	nM	EVETIFATOR
7.99	IC50	10.2	nM	CHEMBL5848845
7.99	IC50	10.3	nM	CHEMBL5741113
7.97	IC50	10.6	nM	CHEMBL5998748
7.94	IC50	11.5	nM	CHEMBL5874344
7.93	IC50	11.7	nM	CHEMBL5595443
7.92	IC50	12	nM	CHEMBL5569682
7.92	IC50	12	nM	CHEMBL5920984
7.91	IC50	12.4	nM	CHEMBL5785440
7.82	IC50	15	nM	CHEMBL5564968
7.74	IC50	18.4	nM	CHEMBL5880333
7.73	IC50	18.8	nM	CHEMBL5934683
7.72	IC50	19.1	nM	CHEMBL5592433
7.70	IC50	19.8	nM	CHEMBL6001944
7.57	IC50	26.9	nM	CHEMBL5826918
7.53	IC50	29.4	nM	CHEMBL5770471
7.51	IC50	30.8	nM	CHEMBL5937622
7.49	IC50	32.2	nM	CHEMBL5855819
7.47	IC50	34	nM	CHEMBL5565662
7.40	IC50	40	nM	CHEMBL5575064
7.28	IC50	52	nM	CHEMBL5574460
7.25	IC50	55.6	nM	CHEMBL5911718
7.24	IC50	58	nM	CHEMBL5570121

PubChem BioAssay actives

40 with measured affinity, of 43 total; 40 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-(4-chlorophenoxy)-N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0004	uM
N-[3-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-[3-(trifluoromethoxy)cyclobutyl]oxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0007	uM
2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[2.2.2]octanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0007	uM
2-(4-chloro-3-fluorophenoxy)-N-[3-[4-[3-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0019	uM
2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[2.2.1]heptanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0023	uM
N-[3-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-[3-(triazol-2-yl)cyclobutyl]oxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0024	uM
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0025	uM
2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0027	uM
6-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]quinoline-2-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0038	uM
2-(4-chloro-3-fluorocyclohexyl)oxy-1-[[3-[[1-hydroxy-2-[3-(trifluoromethyl)cyclobutyl]oxyethyl]amino]-1-bicyclo[1.1.1]pentanyl]amino]ethanol	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0050	uM
N-[3-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-(3-cyanocyclobutyl)oxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0053	uM
N-[3-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-[3-(trifluoromethyl)cyclobutyl]oxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0060	uM
2-(4-chloro-3-fluorophenoxy)-N-[3-[(5S)-2-oxo-5-[3-(trifluoromethoxy)cyclobutyl]-1,3-oxazolidin-3-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0068	uM
N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-6-(trifluoromethyl)quinoline-2-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0081	uM
2-(4-chloro-3-fluorophenoxy)-N-[3-[1-[3-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0085	uM
6-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-3,4-dihydro-2H-chromene-2-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0094	uM
2-(4-chlorophenoxy)-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0098	uM
2-(4-chlorophenoxy)-N-[3-[1-[3-(trifluoromethoxy)cyclobutyl]pyrazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0117	uM
6-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]quinoxaline-2-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0120	uM
N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2-[4-(trifluoromethyl)phenoxy]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0150	uM
2-(4-chloro-3-fluorophenoxy)-N-[3-[2-[3-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0191	uM
N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-cyclobutyloxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0340	uM
N-[3-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-cyclobutyloxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0400	uM
N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2-[[6-(trifluoromethyl)-3-pyridinyl]oxy]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0520	uM
7-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]quinoline-3-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0580	uM
2-(4-fluorophenoxy)-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0610	uM
7-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]isoquinoline-3-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.0680	uM
5-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-1,3-benzoxazole-2-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1030	uM
N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-cyclopropyloxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1060	uM
2-(4-chlorophenoxy)-N-[3-[2-[3-(trifluoromethoxy)cyclobutyl]tetrazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1110	uM
N-[3-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-(3-cyano-3-methylcyclobutyl)oxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1130	uM
2-(4-chlorophenoxy)-N-[1-[2-(4-chlorophenoxy)acetyl]piperidin-4-yl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1410	uM
N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-(cyclobutylmethoxy)acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1440	uM
N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-cyclopentyloxyacetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1590	uM
2-(4-bromophenoxy)-N-[4-(tetrazol-1-yl)phenyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1630	uM
N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-(cyclopropylmethoxy)acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.1830	uM
2-(4-chloro-3-fluorophenoxy)-N-[3-(tetrazol-1-yl)-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.2550	uM
5-chloro-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2,3-dihydro-1-benzofuran-2-carboxamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.3770	uM
2-(4-cyclopropylphenoxy)-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	0.6150	uM
N-[3-[[2-(4-chlorophenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-2-(oxolan-3-yloxy)acetamide	2103110: Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tunicamycin	decreases reaction, increases expression, affects cotreatment, affects reaction, increases phosphorylation	20
4-phenylbutyric acid	decreases reaction, increases expression, decreases expression	13
Acetylcysteine	decreases reaction, increases expression, increases abundance, increases reaction	13
Thapsigargin	affects cotreatment, increases reaction, affects binding, increases activity, decreases reaction (+2 more)	12
sodium arsenite	affects cotreatment, affects binding, increases reaction, decreases expression, increases abundance (+7 more)	11
Rotenone	decreases reaction, increases expression, increases phosphorylation, increases reaction, decreases expression	7
Cyclosporine	increases expression, decreases reaction, decreases expression, affects activity, affects cotreatment (+1 more)	7
Cadmium Chloride	increases expression, increases abundance, affects reaction, decreases response to substance, affects activity (+3 more)	7
Particulate Matter	increases reaction, affects cotreatment, increases abundance, increases expression, affects expression	7
salubrinal	affects cotreatment, decreases expression, decreases reaction, increases expression, increases reaction	5
Glucose	decreases reaction, increases expression, increases response to substance, affects cotreatment, increases reaction	5
bisphenol A	decreases expression, decreases reaction, increases expression, affects expression	4
arsenite	affects binding, increases reaction, increases expression, increases phosphorylation, decreases reaction	4
perfluorooctane sulfonic acid	increases expression	4
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, affects cotreatment, decreases reaction, increases abundance	4
Cisplatin	decreases reaction, increases expression, affects activity, affects cotreatment, decreases response to substance	4
Dronabinol	decreases reaction, increases response to substance, decreases expression, increases expression, affects reaction (+1 more)	4
tris(1,3-dichloro-2-propyl)phosphate	decreases reaction, increases expression	3
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	3
Bortezomib	decreases response to substance, affects binding, increases reaction, decreases reaction, increases expression	3
Amiodarone	decreases expression, increases expression	3
Vehicle Emissions	affects expression, increases reaction, increases expression	3
Benzo(a)pyrene	increases expression, increases methylation, affects activity	3
Capsaicin	affects localization, increases expression, decreases reaction	3
Oxygen	affects activity, affects stability, increases expression, decreases expression	3
Paraquat	increases expression, affects expression, affects reaction, affects cotreatment, decreases expression (+1 more)	3
Tetrachlorodibenzodioxin	decreases reaction, increases activity, affects expression, affects cotreatment, increases expression (+1 more)	3
Tobacco Smoke Pollution	decreases reaction, increases expression	3
1-Methyl-4-phenylpyridinium	increases expression, increases reaction	3
Fenretinide	decreases reaction, increases expression, decreases response to substance, affects expression, affects binding (+1 more)	3

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5545953	Binding	Activation of ATF4 ( unknown origin) expressed in human H4 cells incubated for 24 hrs by reporter gene assay	Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases. — J Med Chem

Cellosaurus cell lines

11 cell lines: 7 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0E8	SEES3-1V human ATF4, clone1	Embryonic stem cell	Male
CVCL_A0E9	SEES3-1V human ATF4, clone2	Embryonic stem cell	Male
CVCL_A0F0	SEES3-1V human ATF4, clone3	Embryonic stem cell	Male
CVCL_C8ST	HeLa S3 ATF4 KO	Cancer cell line	Female
CVCL_C8SX	HeLa S3 CHOP/ATF4/ATF5 triple KO	Cancer cell line	Female
CVCL_D7KP	Ubigene A-549 ATF4 KO	Cancer cell line	Male
CVCL_D8HM	Ubigene HCT 116 ATF4 KO	Cancer cell line	Male
CVCL_D8ZL	Ubigene HEK293 ATF4 KO	Transformed cell line	Female
CVCL_D9Y0	Ubigene HeLa ATF4 KO	Cancer cell line	Female
CVCL_E1R6	HAP1 ATF4 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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