EIF2AK3

Summary

EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3, HGNC:3255) is a protein-coding gene on chromosome 2p11.2, encoding Eukaryotic translation initiation factor 2-alpha kinase 3 (Q9NZJ5). Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR).

The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome.

Source: NCBI Gene 9451 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Wolcott-Rallison syndrome (Definitive, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 978 total — 43 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 72
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_004836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3255
Approved symbol	EIF2AK3
Name	eukaryotic translation initiation factor 2 alpha kinase 3
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	PEK, PERK
Ensembl gene	ENSG00000172071
Ensembl biotype	protein_coding
OMIM	604032
Entrez	9451

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 9 protein_coding_CDS_not_defined, 6 retained_intron, 5 protein_coding, 4 nonsense_mediated_decay

ENST00000303236, ENST00000415570, ENST00000470706, ENST00000478003, ENST00000652099, ENST00000652423, ENST00000652666, ENST00000652736, ENST00000668866, ENST00000681996, ENST00000682103, ENST00000682276, ENST00000682468, ENST00000682603, ENST00000682656, ENST00000682844, ENST00000682892, ENST00000682952, ENST00000683501, ENST00000683663, ENST00000684455, ENST00000684535, ENST00000684642, ENST00000684740

RefSeq mRNA: 2 — MANE Select: NM_004836 NM_001313915, NM_004836

CCDS: CCDS33241

Canonical transcript exons

ENST00000303236 — 17 exons

Exon	Start	End
ENSE00001144232	88626967	88627464
ENSE00001158272	88558917	88558979
ENSE00001158279	88562289	88562390
ENSE00001158284	88570874	88571041
ENSE00001158291	88574666	88575446
ENSE00001158305	88579518	88579640
ENSE00001158315	88583430	88583542
ENSE00001158325	88585841	88586061
ENSE00001158332	88587982	88588104
ENSE00001158336	88588761	88588901
ENSE00001158346	88590443	88590605
ENSE00001158355	88590818	88591052
ENSE00003479143	88595469	88595663
ENSE00003574019	88613724	88613853
ENSE00003624482	88593272	88593405
ENSE00003638733	88576554	88576703
ENSE00003841934	88556741	88557936

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 95.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6604 / max 264.6519, expressed in 1798 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29606	13.5605	1795
29604	0.6695	279
29607	0.2303	100
29605	0.1491	46
29608	0.0510	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	95.57	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.18	gold quality
calcaneal tendon	UBERON:0003701	94.80	gold quality
pylorus	UBERON:0001166	94.68	gold quality
parotid gland	UBERON:0001831	94.50	gold quality
nasal cavity epithelium	UBERON:0005384	94.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.05	gold quality
tibia	UBERON:0000979	93.93	gold quality
colonic mucosa	UBERON:0000317	93.41	gold quality
epithelium of nasopharynx	UBERON:0001951	93.36	gold quality
nasopharynx	UBERON:0001728	93.34	gold quality
nasal cavity mucosa	UBERON:0001826	93.10	gold quality
trachea	UBERON:0003126	93.10	gold quality
palpebral conjunctiva	UBERON:0001812	93.02	gold quality
pancreas	UBERON:0001264	92.95	gold quality
superficial temporal artery	UBERON:0001614	92.57	gold quality
corpus epididymis	UBERON:0004359	92.45	gold quality
jejunal mucosa	UBERON:0000399	92.42	gold quality
cartilage tissue	UBERON:0002418	92.18	gold quality
seminal vesicle	UBERON:0000998	92.08	gold quality
saliva-secreting gland	UBERON:0001044	91.91	gold quality
cardia of stomach	UBERON:0001162	91.80	gold quality
minor salivary gland	UBERON:0001830	91.33	gold quality
tonsil	UBERON:0002372	91.07	gold quality
lower lobe of lung	UBERON:0008949	91.02	gold quality
synovial joint	UBERON:0002217	90.97	gold quality
urethra	UBERON:0000057	90.83	gold quality
rectum	UBERON:0001052	90.63	gold quality
eye	UBERON:0000970	90.61	gold quality
superior surface of tongue	UBERON:0007371	90.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	12.98
E-ANND-3	yes	12.06

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
ATF3	Activation
ATF4	Activation
DDIT3	Activation
FGF2	Activation
HSPA5	Activation
IL6	Activation

Upstream regulators (CollecTRI, top): ERP29, ESR1, STAT1

miRNA regulators (miRDB)

98 targeting EIF2AK3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
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-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-205-3P	99.92	69.92	3165

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Distinct roles in transcription during the mammalian unfolded protein response. (PMID:12014989)
• Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation (PMID:12086964)
• PERK plays a role in hypoxia-induced translational attenuation (PMID:12370288)
• results show that PERK binds to and is also inhibited by the hepatitis C virus envelope protein E2 (PMID:12610133)
• Genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity. (PMID:15220213)
• This pilot study demonstrates an association between the EIF2AK3 gene region and susceptibility to type I diabetes. (PMID:15483661)
• activated by Herpes simplex virus 1 infection (PMID:15650164)
• Inactivation of integrated-stress-response signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2alpha or by a dominant-negative PERK impairs cell survival under extreme hypoxia. (PMID:16148948)
• is the first description of a virus-encoded PERK-specific effector and defines a new strategy by which viruses are able to maintain endoplasmic reticulum homeostasis (PMID:17229688)
• PERK activates glycogen synthase kinase 3 to promote the proteasomal degradation of p53. (PMID:17785458)
• carbon monoxide renders endothelial cells resistant to stress by upregulating Nrf2-dependent HO-1 expression via PERK activation (PMID:17823375)
• 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)
• PERK signaling acts to suppress autophagy and lysosomal dysfunction by increasing the expression of HSP70. (PMID:18216498)
• analysis of endoplasmic reticulum (ER) chaperone regulation and survival of cells compensating for deficiency in the ER stress response kinase, PERK (PMID:18426796)
• The growth-inhibitory function of PERK is preserved in tumors and upon proper reactivation can severely inhibit tumor growth through induction of quiescence. (PMID:18451152)
• 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)
• Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation (PMID:18787411)
• PERK activity inhibits the ER stress-induced apoptotic program through the induction of cellular inhibitor of apoptosis (cIAP1 and cIAP2) proteins (PMID:19029953)
• UV-induced eIF2alpha phosphorylation by activation of both PERK and GCN2 via oxidative stress and l-arginine starvation signaling pathways. (PMID:19586904)
• EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 weeks of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent. (PMID:19837917)
• Findings indicate that GRP78 is a biologic target of vorinostat, and activation of the UPR through PERK phosphorylation contributes toward its antitumor activity. (PMID:20072656)
• Findings indicate that mda-7/IL-24 induces PERK activation that triggers production of ceramide, ceramide synthase 6 and thioredoxin, which in turn promote glioma cell autophagy and cell death. (PMID:20103619)
• this report describe clinical features of six patients with Wolcott-Rallison syndrome from two families carrying the same homozygous mutation (W522X) in the EIF2AK3 gene. (PMID:20202148)
• PERK is essential for radiation-induced autophagy and radiosensitivity in caspase-3/7 double-knockout cells. (PMID:20348950)
• These results indicate that PERK-eIF2alpha pathway is a potential target for therapeutic applications in neurodegenerative diseases including Alzheimer’s disease. (PMID:20463975)
• The PERK signaling pathway plays a major role in the action of fluoride on osteoblasts; the bone response in skeletal fluorosis may be due in part to the PERK signaling pathway. (PMID:20709135)
• early DENV-2 infection triggers and then suppresses PERK-mediated eIF2alpha phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively (PMID:21385877)
• Results identify ERp29 as a novel regulator of PERK and provide evidence for the role of ER resident factors in the regulation of chemotherapeutic efficacy. (PMID:21419175)
• We observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398; in case 2, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (PMID:21518408)
• ETF2AK3 gene mutations can lead to the onset of Wolcott-Rallison syndrome. (PMID:21648287)
• Data show that luminal P-PERK and LC3 levels are reduced in PERK-deficient mammary glands, whereas they are increased in human breast ductal carcinoma in situ. (PMID:21709020)
• Common nonsynonymous sequence variants in EIF2AK3 have a modest effect on endoplasmic reticulum stress response. (PMID:22028037)
• Endoplasmic reticulum stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2. (PMID:22072062)
• H(2)S in inhibiting PTP1B activity and thereby promoting PERK activity during the response to ER stress (PMID:22169477)
• Saturated fatty acid-induced ER stress and apoptosis in these human liver cells were enacted through the PERK/ATF4/CHOP signaling pathway. (PMID:22246806)
• Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK). (PMID:22253692)
• ubtilase cytotoxin -induced ER stress is caused by BiP cleavage, leading to PERK activation, not by accumulation of ubiquitinated proteins, which undergo PERK-dependent degradation via the ubiquitin-proteasome system. (PMID:22354021)
• BiP binds to IRE1 and PERK in a different manner. (PMID:22446326)
• PERK plays a critical role in information processing and cognitive function and that modulation of eIF2alpha phosphorylation and ATF4 expression. (PMID:22813743)
• results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. (PMID:22915762)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2ak3	ENSDARG00000062139
mus_musculus	Eif2ak3	ENSMUSG00000031668
rattus_norvegicus	Eif2ak3	ENSRNOG00000006069
drosophila_melanogaster	Wee1	FBGN0011737

Paralogs (8): EIF2AK2 (ENSG00000055332), EIF2AK1 (ENSG00000086232), STK35 (ENSG00000125834), PKMYT1 (ENSG00000127564), EIF2AK4 (ENSG00000128829), WEE1 (ENSG00000166483), PDIK1L (ENSG00000175087), WEE2 (ENSG00000214102)

Protein

Protein identifiers

Eukaryotic translation initiation factor 2-alpha kinase 3 — Q9NZJ5 (reviewed: Q9NZJ5)

Alternative names: PRKR-like endoplasmic reticulum kinase, Pancreatic eIF2-alpha kinase, Protein tyrosine kinase EIF2AK3

All UniProt accessions (9): Q9NZJ5, A0A494BZR8, A0A494C186, A0A804HI66, A0A804HIT4, A0A804HJ50, A0A804HJV6, A0A804HL08, A0A804HLC2

UniProt curated annotations — full annotation on UniProt →

Function. Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR). Key effector of the integrated stress response (ISR) to unfolded proteins: EIF2AK3/PERK specifically recognizes and binds misfolded proteins, leading to its activation and EIF2S1/eIF-2-alpha phosphorylation. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming. The EIF2AK3/PERK-mediated unfolded protein response increases mitochondrial oxidative phosphorylation by promoting ATF4-mediated expression of COX7A2L/SCAF1, thereby increasing formation of respiratory chain supercomplexes. In contrast to most subcellular compartments, mitochondria are protected from the EIF2AK3/PERK-mediated unfolded protein response due to EIF2AK3/PERK inhibition by ATAD3A at mitochondria-endoplasmic reticulum contact sites. In addition to EIF2S1/eIF-2-alpha, also phosphorylates NFE2L2/NRF2 in response to stress, promoting release of NFE2L2/NRF2 from the BCR(KEAP1) complex, leading to nuclear accumulation and activation of NFE2L2/NRF2. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function.

Subunit / interactions. Forms dimers with HSPA5/BIP in resting cells. Homotetramerizes in response to endoplasmic reticulum (ER) stress, leading to its activation. Interacts with HSP90B1/GRP94. Interacts with DNAJC3; inhibiting EIF2AK3/PERK activity. Interacts with ATAD3A; ATAD3A and EIF2S1/eIF-2-alpha occupy a common binding site within the cytoplasmic loop of EIF2AK3/PERK, leading to prevent EIF2AK3/PERK association with its substrate EIF2S1/eIF-2-alpha. Interacts with MFN2. Interacts with TMEM33. Interacts with PDIA6. Interacts with LACC1.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous. A high level expression is seen in secretory tissues.

Post-translational modifications. Oligomerization of the N-terminal ER luminal domain by ER stress promotes EIF2AK3/PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop. Autophosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its activity. Dephosphorylated at Tyr-619 by PTPN1/PTP1B, leading to inactivate its enzyme activity. Phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK. ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.

Disease relevance. Wolcott-Rallison syndrome (WRS) [MIM:226980] A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, intellectual disability and cardiovascular abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by HSPA5/BIP in absence of stress. Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in trans-autophosphorylation and kinase activity induction. Inactivated following phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3). Inhibited by ATAD3A at mitochondria-endoplasmic reticulum contact sites, providing a safe haven for mitochondrial protein translation during ER stress.

Domain organisation. The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP. The insert loop specifically recongnizes and binds EIF2S1/eIF-2-alpha.

Induction. By endoplasmic reticulum stress.

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

RefSeq proteins (2): NP_001300844, NP_004827* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050339	CC_SR_Kinase	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 3 shown:

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

UniProt features (91 total): strand 27, helix 16, sequence variant 15, region of interest 5, modified residue 5, turn 5, mutagenesis site 4, compositionally biased region 2, binding site 2, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, active site 1, glycosylation site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
4X7K	X-RAY DIFFRACTION	1.8
4X7L	X-RAY DIFFRACTION	1.9
4X7H	X-RAY DIFFRACTION	2
4G31	X-RAY DIFFRACTION	2.28
4X7J	X-RAY DIFFRACTION	2.3
4M7I	X-RAY DIFFRACTION	2.34
4X7N	X-RAY DIFFRACTION	2.35
8EQE	X-RAY DIFFRACTION	2.56
4X7O	X-RAY DIFFRACTION	2.65
4G34	X-RAY DIFFRACTION	2.7
7MF0	X-RAY DIFFRACTION	2.81
8EQ9	X-RAY DIFFRACTION	2.86
8EQD	X-RAY DIFFRACTION	2.92
4YZS	X-RAY DIFFRACTION	3.14
5SV7	X-RAY DIFFRACTION	3.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZJ5-F1	59.85	0.16

Functional residue map

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

Catalytic / active sites (1): 937 (proton acceptor)

Ligand- & substrate-binding residues (2): 599–607; 622

Post-translational modifications (5): 619, 715, 802, 982, 1094

Glycosylation sites (1): 258

Mutagenesis-validated functional residues (4):

Position	Phenotype
164	decreased tetramerization and activation, leading to decreased ability to phosphorylate eif2s1/eif-2-alpha.
388	decreased tetramerization and activation, leading to decreased ability to phosphorylate eif2s1/eif-2-alpha.
395	decreased tetramerization and activation, leading to decreased ability to phosphorylate eif2s1/eif-2-alpha.
397	decreased tetramerization and activation, leading to decreased ability to phosphorylate eif2s1/eif-2-alpha.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-381042	PERK regulates gene expression
R-HSA-9700645	ALK mutants bind TKIs
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9909505	Modulation of host responses by IFN-stimulated genes

MSigDB gene sets: 573 (showing top): MODULE_97, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, GOBP_CARTILAGE_DEVELOPMENT, CCAWYNNGAAR_UNKNOWN, GOBP_RESPONSE_TO_COLD, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, MODULE_182, GOBP_TRANSLATIONAL_INITIATION

GO Biological Process (36): skeletal system development (GO:0001501), ossification (GO:0001503), angiogenesis (GO:0001525), chondrocyte development (GO:0002063), regulation of translational initiation (GO:0006446), ER overload response (GO:0006983), endoplasmic reticulum organization (GO:0007029), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), negative regulation of translation (GO:0017148), calcium-mediated signaling (GO:0019722), bone mineralization (GO:0030282), endoplasmic reticulum unfolded protein response (GO:0030968), endocrine pancreas development (GO:0031018), negative regulation of myelination (GO:0031642), negative regulation of translation in response to stress (GO:0032055), negative regulation of translational initiation in response to stress (GO:0032057), cellular response to amino acid starvation (GO:0034198), response to endoplasmic reticulum stress (GO:0034976), regulation of translation initiation in response to endoplasmic reticulum stress (GO:0036491), PERK-mediated unfolded protein response (GO:0036499), cellular response to glucose starvation (GO:0042149), positive regulation of transcription by RNA polymerase I (GO:0045943), negative regulation of translational initiation (GO:0045947), insulin-like growth factor receptor signaling pathway (GO:0048009), cellular response to cold (GO:0070417), positive regulation of protein localization to nucleus (GO:1900182), regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902235), response to manganese-induced endoplasmic reticulum stress (GO:1990737), translational initiation (GO:0006413), regulation of translation (GO:0006417), protein phosphorylation (GO:0006468), response to oxidative stress (GO:0006979), response to unfolded protein (GO:0006986), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), mitochondrial respirasome assembly (GO:0097250)

GO Molecular Function (17): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), eukaryotic translation initiation factor 2alpha kinase activity (GO:0004694), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein phosphatase binding (GO:0019903), identical protein binding (GO:0042802), translation regulator activity (GO:0045182), misfolded protein binding (GO:0051787), Hsp90 protein binding (GO:0051879), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), perinuclear region of cytoplasm (GO:0048471), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by ALK in cancer	2
Unfolded Protein Response (UPR)	1
Cellular response to chemical stress	1
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	4
translational initiation	3
regulation of translation	3
response to endoplasmic reticulum stress	3
protein kinase activity	3
protein binding	3
intracellular membrane-bounded organelle	3
translation	2
cellular response to stress	2
system development	1
multicellular organismal process	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
chondrocyte differentiation	1
cell development	1
ER-nucleus signaling pathway	1
cellular response to biotic stimulus	1
organelle organization	1
endomembrane system organization	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
intracellular signaling cassette	1
ossification	1
biomineral tissue development	1
cellular response to unfolded protein	1
intracellular signal transduction	1
pancreas development	1
endocrine system development	1
anatomical structure development	1
regulation of myelination	1
negative regulation of nervous system process	1
myelination	1
negative regulation of cellular process	1

Protein interactions and networks

STRING

3674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2AK3	HSPA5	P11021	999
EIF2AK3	EIF2S1	P05198	974
EIF2AK3	ATF6	P18850	971
EIF2AK3	ATF4	P18848	928
EIF2AK3	PPP1R15A	O75807	901
EIF2AK3	HSP90B1	P14625	901
EIF2AK3	XBP1	P17861	892
EIF2AK3	DDIT3	P35638	880
EIF2AK3	HSP90AA1	P07900	813
EIF2AK3	HSP90AB1	P08238	810
EIF2AK3	ALPK3	Q96L96	791
EIF2AK3	ACTB	P02570	772
EIF2AK3	CASP3	P42574	769
EIF2AK3	PDIA6	Q15084	751
EIF2AK3	ATF6B	Q99941	750

IntAct

117 interactions, top by confidence:

A	B	Type	Score
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
TGIF2LY	PGP	psi-mi:“MI:0914”(association)	0.640
EIF2AK3	HSPA5	psi-mi:“MI:0915”(physical association)	0.590
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
RPN2	SMPD2	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
OGFOD3	CLGN	psi-mi:“MI:0914”(association)	0.530
EIF2AK3	EIF2AK3	psi-mi:“MI:0915”(physical association)	0.520
HSP90B1	EIF2AK3	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK3	EIF2A	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK3		psi-mi:“MI:0915”(physical association)	0.370
FOXK1	PHKG2	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
PCDHA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA9	TMEM120B	psi-mi:“MI:0914”(association)	0.350
DLK2	SLC22A23	psi-mi:“MI:0914”(association)	0.350
PCDHA12	KLRG2	psi-mi:“MI:0914”(association)	0.350
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.350

BioGRID (227): EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Proximity Label-MS), EIF2AK3 (Proximity Label-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), NFE2L2 (Two-hybrid), EIF2AK3 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Q3S9, A2VCV0, A9ULX8, E1BN97, F1NVK6, F6UF99, P28236, P79169, P79368, Q06220, Q09108, Q0P557, Q0VA42, Q1LZF8, Q28132, Q29030, Q2T9I9, Q3B7T8, Q3V0J1, Q5PQX1, Q5R6R3, Q5T5J6, Q5ZM60, Q640L3, Q640U0, Q66H73, Q6PAV5, Q6PG04, Q7ZX27, Q7ZXV6, Q8K4Q9, Q8N4S0, Q8TDY2, Q90314, Q90WN7, Q91892, Q921T2, Q95M19, Q95MD2, Q95N18

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

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
EIF2AK3	up-regulates	EIF2AK3	phosphorylation
EIF2AK3	down-regulates	EIF2S1	phosphorylation
EIF2AK3	“down-regulates activity”	EIF2S1	phosphorylation
DNAJC3	“down-regulates activity”	EIF2AK3	binding
HSPA5	“down-regulates activity”	EIF2AK3	binding
S	“up-regulates activity”	EIF2AK3
PTPN1	“down-regulates activity”	EIF2AK3	dephosphorylation
EIF2AK3	“down-regulates activity”	PPP3CA	phosphorylation
EIF2AK3	“up-regulates activity”	OGT	phosphorylation
EIF2AK3	“up-regulates activity”	DLG4	phosphorylation
SOD1	“up-regulates activity”	EIF2AK3	binding
JAK1	“up-regulates activity”	EIF2AK3	phosphorylation
PDIA6	“down-regulates activity”	EIF2AK3
RHEB	“down-regulates activity”	EIF2AK3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	7	41.8×	5e-08
Maturation of spike protein	8	24.4×	1e-07
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	6	23.2×	2e-05
Maturation of DENV proteins	9	21.9×	5e-08
Downstream TCR signaling	6	8.8×	3e-03
Asparagine N-linked glycosylation	9	6.2×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	6	34.3×	1e-05
membrane depolarization	5	21.6×	8e-04
protein N-linked glycosylation	7	15.6×	1e-04
ERAD pathway	6	9.2×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	44
Uncertain significance	355
Likely benign	449
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1175193	NM_004836.7(EIF2AK3):c.12del (p.Ile5fs)	Pathogenic
1179141	NM_004836.7(EIF2AK3):c.1936_1958del (p.Leu646fs)	Pathogenic
1445792	NM_004836.7(EIF2AK3):c.1534A>T (p.Lys512Ter)	Pathogenic
1453040	NM_004836.7(EIF2AK3):c.495_498del (p.Asp165fs)	Pathogenic
1454333	NM_004836.7(EIF2AK3):c.2636C>G (p.Ser879Ter)	Pathogenic
1458176	NM_004836.7(EIF2AK3):c.496C>T (p.Gln166Ter)	Pathogenic
1995815	NM_004836.7(EIF2AK3):c.1657A>T (p.Lys553Ter)	Pathogenic
2014775	NM_004836.7(EIF2AK3):c.262del (p.Arg88fs)	Pathogenic
2030634	NM_004836.7(EIF2AK3):c.3025_3029del (p.Ser1009fs)	Pathogenic
2033149	NM_004836.7(EIF2AK3):c.1824del (p.Phe608fs)	Pathogenic
2048813	NM_004836.7(EIF2AK3):c.496_497inv (p.Gln166Ter)	Pathogenic
208168	NM_004836.7(EIF2AK3):c.1192C>T (p.Gln398Ter)	Pathogenic
210932	NM_004836.7(EIF2AK3):c.1564_1565del (p.Trp522fs)	Pathogenic
2203114	NM_004836.7(EIF2AK3):c.989_990insT (p.Glu330fs)	Pathogenic
2505984	NM_004836.7(EIF2AK3):c.1694_1695del (p.Lys564_Tyr565insTer)	Pathogenic
2675010	NM_004836.7(EIF2AK3):c.1912C>T (p.Arg638Ter)	Pathogenic
2675018	NM_004836.7(EIF2AK3):c.2729_2732del (p.Glu910fs)	Pathogenic
2675024	NM_004836.7(EIF2AK3):c.1563G>A (p.Trp521Ter)	Pathogenic
2697767	NM_004836.7(EIF2AK3):c.3029T>G (p.Leu1010Ter)	Pathogenic
2707315	NM_004836.7(EIF2AK3):c.1835del (p.Asn612fs)	Pathogenic
2714050	NM_004836.7(EIF2AK3):c.2921del (p.Pro974fs)	Pathogenic
2729968	NM_004836.7(EIF2AK3):c.3150+1G>A	Pathogenic
2734241	NM_004836.7(EIF2AK3):c.3193C>T (p.Arg1065Ter)	Pathogenic
2734243	NM_004836.7(EIF2AK3):c.1474C>T (p.Arg492Ter)	Pathogenic
2734341	NM_004836.7(EIF2AK3):c.1216_1217del (p.Lys406fs)	Pathogenic
2734822	NM_004836.7(EIF2AK3):c.1999dup (p.Gln667fs)	Pathogenic
2737880	NM_004836.7(EIF2AK3):c.88_139dup (p.Leu47fs)	Pathogenic
2748910	NM_004836.7(EIF2AK3):c.1842_1845dup (p.Asp616delinsArgTer)	Pathogenic
2754870	NM_004836.7(EIF2AK3):c.627_628dup (p.Gly210fs)	Pathogenic
2767802	NM_004836.7(EIF2AK3):c.3141T>A (p.Tyr1047Ter)	Pathogenic

SpliceAI

2646 predictions. Top by Δscore:

Variant	Effect	Δscore
2:88557933:CGTA:C	acceptor_gain	1.0000
2:88557935:TA:T	acceptor_gain	1.0000
2:88557937:C:CC	acceptor_gain	1.0000
2:88558912:CATA:C	donor_loss	1.0000
2:88558915:ACCT:A	donor_loss	1.0000
2:88558916:C:G	donor_loss	1.0000
2:88558977:GGT:G	acceptor_gain	1.0000
2:88558977:GGTC:G	acceptor_loss	1.0000
2:88558978:GT:G	acceptor_gain	1.0000
2:88558979:TCTA:T	acceptor_loss	1.0000
2:88558980:C:CC	acceptor_gain	1.0000
2:88558980:CTAA:C	acceptor_loss	1.0000
2:88562287:AC:A	donor_gain	1.0000
2:88562288:CC:C	donor_gain	1.0000
2:88571039:TGG:T	acceptor_gain	1.0000
2:88571039:TGGC:T	acceptor_loss	1.0000
2:88571040:GG:G	acceptor_gain	1.0000
2:88571040:GGCTG:G	acceptor_loss	1.0000
2:88571041:GCTG:G	acceptor_loss	1.0000
2:88571042:C:A	acceptor_loss	1.0000
2:88571042:C:CC	acceptor_gain	1.0000
2:88571051:A:AC	acceptor_gain	1.0000
2:88571051:A:C	acceptor_gain	1.0000
2:88574662:AGAC:A	donor_loss	1.0000
2:88574663:GAC:G	donor_loss	1.0000
2:88574664:A:AG	donor_loss	1.0000
2:88574665:CCT:C	donor_loss	1.0000
2:88574693:A:AC	donor_gain	1.0000
2:88574694:C:CC	donor_gain	1.0000
2:88575442:CTGTG:C	acceptor_gain	1.0000

AlphaMissense

7357 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:88570994:G:C	D955E	1.000
2:88570994:G:T	D955E	1.000
2:88570995:T:A	D955V	1.000
2:88570995:T:C	D955G	1.000
2:88570995:T:G	D955A	1.000
2:88570996:C:G	D955H	1.000
2:88571031:A:T	I943K	1.000
2:88571033:G:C	N942K	1.000
2:88571033:G:T	N942K	1.000
2:88574670:A:G	L938P	1.000
2:88574672:G:C	D937E	1.000
2:88574672:G:T	D937E	1.000
2:88574673:T:A	D937V	1.000
2:88574673:T:C	D937G	1.000
2:88574673:T:G	D937A	1.000
2:88574832:A:G	L884P	1.000
2:88576635:A:T	V652D	1.000
2:88579538:C:A	K622N	1.000
2:88579538:C:G	K622N	1.000
2:88579540:T:C	K622E	1.000
2:88579545:G:T	A620D	1.000
2:88579576:C:G	A610P	1.000
2:88579590:C:T	G605E	1.000
2:88579592:A:C	F604L	1.000
2:88579592:A:T	F604L	1.000
2:88579594:A:G	F604L	1.000
2:88613778:C:A	W128C	1.000
2:88613778:C:G	W128C	1.000
2:88562344:C:T	G1011D	0.999
2:88562345:C:G	G1011R	0.999

dbSNP variants (sampled 300 via entrez): RS1000024440 (2:88593866 A>G), RS1000041478 (2:88589879 G>A), RS1000048190 (2:88591445 A>G), RS1000248160 (2:88596874 G>A), RS1000275852 (2:88598776 T>C), RS1000311459 (2:88563639 T>C), RS1000326852 (2:88583719 C>T), RS1000339430 (2:88611358 T>C), RS1000397095 (2:88599087 A>C), RS1000442159 (2:88604169 C>G), RS1000473551 (2:88604496 CT>C), RS1000480696 (2:88621109 T>A,C), RS1000535951 (2:88621422 A>G), RS1000536692 (2:88570511 A>G), RS1000590020 (2:88563359 C>G)

Disease associations

OMIM: gene MIM:604032 | disease phenotypes: MIM:226980, MIM:309400

GenCC curated gene-disease

Disease	Classification	Inheritance
Wolcott-Rallison syndrome	Definitive	Autosomal recessive

Mondo (4): Wolcott-Rallison syndrome (MONDO:0009192), connective tissue disorder (MONDO:0003900), monogenic diabetes (MONDO:0015967), Menkes disease (MONDO:0010651)

Orphanet (3): Wolcott-Rallison syndrome (Orphanet:1667), Rare genetic diabetes mellitus (Orphanet:183625), Menkes disease (Orphanet:565)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000486	Strabismus
HP:0000582	Upslanted palpebral fissure
HP:0000821	Hypothyroidism
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000857	Neonatal insulin-dependent diabetes mellitus
HP:0000926	Platyspondyly
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001392	Abnormality of the liver
HP:0001498	Carpal bone hypoplasia
HP:0001510	Growth delay
HP:0001541	Ascites
HP:0001552	Barrel-shaped chest
HP:0001631	Atrial septal defect
HP:0001719	Double outlet right ventricle
HP:0001738	Exocrine pancreatic insufficiency
HP:0001875	Decreased total neutrophil count
HP:0001891	Iron deficiency anemia
HP:0001944	Dehydration

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000817_8	Height	1.000000e-13
GCST001116_2	Progressive supranuclear palsy	4.000000e-13
GCST002647_79	Height	9.000000e-25
GCST002702_114	Height	2.000000e-14
GCST007576_169	Chronotype	6.000000e-09
GCST008839_331	Height	1.000000e-23
GCST009028_26	Adverse response to drug	1.000000e-09
GCST012227_1202	Hip circumference adjusted for BMI	3.000000e-11
GCST90000025_758	Appendicular lean mass	1.000000e-18
GCST90000026_18	Appendicular lean mass	2.000000e-07
GCST90000027_6	Appendicular lean mass	2.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0009658	adverse effect
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D007706	Menkes Kinky Hair Syndrome	C10.228.140.163.100.540; C10.597.606.360.455.687; C16.320.322.500.687; C16.320.400.525.687; C16.320.565.189.540; C16.320.565.618.590; C17.800.329.968; C18.452.132.100.540; C18.452.648.189.540; C18.452.648.618.590
C536739	Wolcott-Rallison syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6030 (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: 348 (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
CHEMBL4068509	PRN-1371	1	348

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — PEK subfamily

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

Ligand	Action	Affinity	Parameter
GSK2606414	Inhibition	9.4	pIC50
GSK2656157	Inhibition	9.1	pIC50
HC-5404	Inhibition	8.4	pIC50

Binding affinities (BindingDB)

108 measured of 115 human assays (115 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4R)-8-[3-[3-chloro-2-(methylamino)-4-pyridinyl]-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	20 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4R)-8-[3-(2-chloro-3-methoxyphenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	34 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(3R)-8-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-3-fluoro-8-azaspiro[4.5]decan-4-amine	IC50	34 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4R)-8-[3-(3-amino-2-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	35 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4S)-8-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine	IC50	40 nM	US-10280171: Heterocyclic inhibitors of PTPN11
[1-[3-(3-chloro-2-fluorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl]methanamine	IC50	47 nM	US-10280171: Heterocyclic inhibitors of PTPN11
4-[6-[4-(aminomethyl)-4-methylpiperidin-1-yl]-2H-pyrazolo[3,4-b]pyrazin-3-yl]-3-chloro-N-methylpyridin-2-amine	IC50	47 nM	US-10280171: Heterocyclic inhibitors of PTPN11
[4-amino-1-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]piperidin-4-yl]methanol	IC50	53 nM	US-10280171: Heterocyclic inhibitors of PTPN11
4-chloro-3-[1-ethyl-2-oxo-7-[2-(prop-2-enoylamino)phenyl]-1,6-naphthyridin-3-yl]-N-methoxybenzamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[4-fluoro-3-[3-(2-fluoro-3,5-dimethoxyphenyl)-2-oxo-1-propan-2-yl-1,6-naphthyridin-7-yl]phenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
1-[6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]-5-fluoro-2,3-dihydroindol-1-yl]prop-2-en-1-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[2-[3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,6-naphthyridin-7-yl]phenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[3-[3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-4H-pyrido[4,3-d]pyrimidin-7-yl]phenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[3-[3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,6-naphthyridin-7-yl]-4-fluorophenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
1-[6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]-7-methyl-2,3-dihydro-1,4-benzoxazin-4-yl]prop-2-en-1-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[2-[3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-1-propan-2-yl-1,6-naphthyridin-7-yl]phenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[3-[3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,6-naphthyridin-7-yl]-4-methylphenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
1-[6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]-7-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl]prop-2-en-1-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
N-[3-[3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-4H-pyrido[4,3-d]pyrimidin-7-yl]-4-fluorophenyl]prop-2-enamide	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
1-[6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]-2,2-dimethyl-3H-1,4-benzoxazin-4-yl]prop-2-en-1-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(1-prop-2-enoyl-2,3-dihydroindol-6-yl)pyrido[2,3-d]pyrimidin-7-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-prop-2-enoyl-2,3-dihydro-1,4-benzoxazin-6-yl)-1,6-naphthyridin-2-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(4-prop-2-enoyl-2,3-dihydro-1,4-benzoxazin-6-yl)-4H-pyrido[4,3-d]pyrimidin-2-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(2,2-dimethyl-4-prop-2-enoyl-3H-1,4-benzoxazin-6-yl)-1-ethyl-1,6-naphthyridin-2-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-7-(7-fluoro-3-methyl-4-prop-2-enoyl-2,3-dihydro-1,4-benzoxazin-6-yl)-1,6-naphthyridin-2-one	IC50	55 nM	US-9695165: Inhibitors of the fibroblast growth factor receptor
[1-[3-(2-chloro-3-methoxyphenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl]methanamine	IC50	55 nM	US-10280171: Heterocyclic inhibitors of PTPN11
4-[6-(4-amino-4-methylpiperidin-1-yl)-2H-pyrazolo[3,4-b]pyrazin-3-yl]-3-chloro-N-methylpyridin-2-amine	IC50	58 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4R)-8-[3-(3-chloro-2-fluorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	62 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4S)-8-[3-(2-chloro-3-fluorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine	IC50	63 nM	US-10280171: Heterocyclic inhibitors of PTPN11
3-[6-[4-(aminomethyl)-4-methylpiperidin-1-yl]-2H-pyrazolo[3,4-b]pyrazin-3-yl]-2-chloroaniline	IC50	63 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4R)-8-[3-(2-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	64 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4R)-8-[3-(2-amino-3-chloro-4-pyridinyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	65 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(3S)-8-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-3-fluoro-8-azaspiro[4.5]decan-4-amine	IC50	70 nM	US-10280171: Heterocyclic inhibitors of PTPN11
6-(1,7-diazaspiro[3.5]nonan-7-yl)-3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazine	IC50	79 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4R)-8-[3-(4-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-4-amine	IC50	82 nM	US-10280171: Heterocyclic inhibitors of PTPN11
4-(aminomethyl)-1-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]piperidin-4-ol	IC50	86 nM	US-10280171: Heterocyclic inhibitors of PTPN11
[1-[3-(2-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl]methanamine	IC50	87 nM	US-10280171: Heterocyclic inhibitors of PTPN11
[1-[3-(4-chloro-3-methoxyphenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl]methanamine	IC50	96 nM	US-10280171: Heterocyclic inhibitors of PTPN11
N-[(1R)-1-[1-[6-chloro-5-[3-chloro-2-[(4-methoxyphenyl)methylamino]pyridine-4-carbonyl]pyrazin-2-yl]-4-methylpiperidin-4-yl]ethyl]-2-methylpropane-2-sulfinamide	IC50	100 nM	US-10280171: Heterocyclic inhibitors of PTPN11
1-[3-(4-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine	IC50	103 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4S)-8-[3-(2-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine	IC50	103 nM	US-10280171: Heterocyclic inhibitors of PTPN11
1-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-(fluoromethyl)piperidin-4-amine	IC50	109 nM	US-10280171: Heterocyclic inhibitors of PTPN11
1-[3-(3-amino-2-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine	IC50	120 nM	US-10280171: Heterocyclic inhibitors of PTPN11
4-[6-(4-amino-4-ethylpiperidin-1-yl)-2H-pyrazolo[3,4-b]pyrazin-3-yl]-3-chloropyridin-2-amine	IC50	122 nM	US-10280171: Heterocyclic inhibitors of PTPN11
1-[3-(2-chloro-3-fluorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine	IC50	142 nM	US-10280171: Heterocyclic inhibitors of PTPN11
1-[3-(2-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine	IC50	158 nM	US-10280171: Heterocyclic inhibitors of PTPN11
8-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-3,3-difluoro-8-azaspiro[4.5]decan-4-amine	IC50	165 nM	US-10280171: Heterocyclic inhibitors of PTPN11
1-[3-(3-chlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine	IC50	172 nM	US-10280171: Heterocyclic inhibitors of PTPN11
4-[6-(4-amino-4-methylpiperidin-1-yl)-2H-pyrazolo[3,4-b]pyrazin-3-yl]-3-chloropyridin-2-amine	IC50	174 nM	US-10280171: Heterocyclic inhibitors of PTPN11
(4S)-8-[3-(2-chloro-6-fluorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine	IC50	186 nM	US-10280171: Heterocyclic inhibitors of PTPN11

ChEMBL bioactivities

282 potent at pChembl≥5 of 283 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL2171126
9.70	IC50	0.2	nM	CHEMBL2171122
9.70	IC50	0.2	nM	CHEMBL2171144
9.70	IC50	0.2	nM	CHEMBL2171143
9.70	IC50	0.2	nM	CHEMBL2171141
9.52	IC50	0.3	nM	CHEMBL2171125
9.40	IC50	0.4	nM	CHEMBL2171124
9.40	IC50	0.4	nM	CHEMBL2171139
9.40	IC50	0.3981	nM	CHEMBL3355039
9.30	IC50	0.5	nM	CHEMBL2171123
9.30	IC50	0.5	nM	CHEMBL2441342
9.30	IC50	0.5	nM	CHEMBL2441341
9.22	IC50	0.6	nM	CHEMBL2171135
9.20	IC50	0.631	nM	CHEMBL3355038
9.15	IC50	0.7	nM	CHEMBL2171140
9.10	IC50	0.8	nM	CHEMBL2441340
9.10	IC50	0.7943	nM	CHEMBL3355037
9.05	IC50	0.9	nM	CHEMBL2171121
9.05	IC50	0.9	nM	CHEMBL2171131
9.00	IC50	1	nM	CHEMBL3355046
9.00	IC50	1	nM	CHEMBL3407849
9.00	IC50	1	nM	CHEMBL3407846
8.92	IC50	1.2	nM	CHEMBL2171129
8.89	IC50	1.3	nM	CHEMBL2171132
8.82	IC50	1.5	nM	CHEMBL2171142
8.80	IC50	1.585	nM	CHEMBL3355040
8.72	IC50	1.9	nM	CHEMBL2171130
8.72	IC50	1.9	nM	CHEMBL2441345
8.70	IC50	2	nM	CHEMBL3407863
8.70	IC50	2	nM	CHEMBL4857782
8.60	IC50	2.5	nM	CHEMBL2171134
8.60	IC50	2.5	nM	CHEMBL2441339
8.57	IC50	2.7	nM	CHEMBL2441346
8.52	IC50	3	nM	CHEMBL3407850
8.52	IC50	3	nM	CHEMBL3407504
8.52	IC50	3	nM	CHEMBL4869882
8.52	IC50	3	nM	CHEMBL4853221
8.52	IC50	3	nM	CHEMBL4870780
8.50	IC50	3.162	nM	CHEMBL3355041
8.49	IC50	3.2	nM	CHEMBL2171128
8.42	IC50	3.8	nM	CHEMBL2441341
8.40	IC50	4	nM	CHEMBL3407856
8.40	IC50	4	nM	CHEMBL3407852
8.40	IC50	4	nM	CHEMBL3407848
8.40	IC50	4	nM	CHEMBL4862478
8.40	IC50	4	nM	CHEMBL4863698
8.39	IC50	4.1	nM	CHEMBL1667910
8.30	IC50	5.012	nM	CHEMBL3355043
8.30	IC50	5	nM	CHEMBL3407854
8.30	IC50	5	nM	CHEMBL3407851

PubChem BioAssay actives

243 with measured affinity, of 438 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-fluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0002	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-chlorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0002	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2-methylphenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0002	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-methylphenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0002	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2,3,5-trifluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0002	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0003	uM
2-(2,5-difluorophenyl)-1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,3-dihydroindol-1-yl]ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0004	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0004	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0004	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3-methoxyphenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0005	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-[6-(trifluoromethyl)-2-pyridinyl]ethanone	777348: Inhibition of GST-tagged PERK cytoplasmic domain (536 to 1116) (unknown origin) assessed as biotinylated His6-tagged EIF2alpha phosphorylation preincubated for 30 mins followed by ATP and eIF2alpha addition measured after 1 hr by HTRF assay	ic50	0.0005	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[6-(trifluoromethyl)-2-pyridinyl]ethanone	777348: Inhibition of GST-tagged PERK cytoplasmic domain (536 to 1116) (unknown origin) assessed as biotinylated His6-tagged EIF2alpha phosphorylation preincubated for 30 mins followed by ATP and eIF2alpha addition measured after 1 hr by HTRF assay	ic50	0.0005	uM
1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,3-dihydroindol-1-yl]-2-(6-fluoro-2-methyl-1H-indol-3-yl)ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0006	uM
1-[5-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0006	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2-fluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0007	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-(6-methyl-2-pyridinyl)ethanone	777348: Inhibition of GST-tagged PERK cytoplasmic domain (536 to 1116) (unknown origin) assessed as biotinylated His6-tagged EIF2alpha phosphorylation preincubated for 30 mins followed by ATP and eIF2alpha addition measured after 1 hr by HTRF assay	ic50	0.0008	uM
1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,3-dihydroindol-1-yl]-2-(2-methyl-1H-indol-3-yl)ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0008	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2-chlorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0009	uM
1-[5-[4-amino-7-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl]-2,3-dihydroindol-1-yl]-2-phenylethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0009	uM
2-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0010	uM
1-methyl-4-[4-methyl-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0010	uM
1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluoro-2,3-dihydroindol-1-yl]-2-(2-methyl-1H-indol-3-yl)ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0010	uM
1-[5-(4-amino-7-pyridin-4-ylthieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-phenylethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0012	uM
1-[5-[4-amino-7-(1-methylpyrazol-4-yl)thieno[3,2-c]pyridin-3-yl]-2,3-dihydroindol-1-yl]-2-phenylethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0013	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(4-fluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0015	uM
1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,3-dihydroindol-1-yl]-2-(7-fluoro-2-methyl-1H-indol-3-yl)ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0016	uM
1-[5-(4-amino-7-piperidin-4-ylthieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-phenylethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0019	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(3,5-dimethylpyrazol-1-yl)ethanone	777348: Inhibition of GST-tagged PERK cytoplasmic domain (536 to 1116) (unknown origin) assessed as biotinylated His6-tagged EIF2alpha phosphorylation preincubated for 30 mins followed by ATP and eIF2alpha addition measured after 1 hr by HTRF assay	ic50	0.0019	uM
2-[5-(4-amino-2,7-dimethylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0020	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-ethylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0020	uM
1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0025	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(6-methyl-2-pyridinyl)ethanone	777348: Inhibition of GST-tagged PERK cytoplasmic domain (536 to 1116) (unknown origin) assessed as biotinylated His6-tagged EIF2alpha phosphorylation preincubated for 30 mins followed by ATP and eIF2alpha addition measured after 1 hr by HTRF assay	ic50	0.0025	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-(3,5-dimethylpyrazol-1-yl)ethanone	777348: Inhibition of GST-tagged PERK cytoplasmic domain (536 to 1116) (unknown origin) assessed as biotinylated His6-tagged EIF2alpha phosphorylation preincubated for 30 mins followed by ATP and eIF2alpha addition measured after 1 hr by HTRF assay	ic50	0.0027	uM
4-[2-amino-4-methyl-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0030	uM
4-[4-amino-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0030	uM
2-amino-N-cyclopropyl-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]pyridine-3-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0030	uM
2-amino-5-[4-[[(2R)-2-(3-chlorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0030	uM
2-amino-5-[4-[[(2R)-2-hydroxy-2-(3-methylphenyl)acetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0030	uM
1-[5-(4-amino-7-pyridin-3-ylthieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-phenylethanone	702110: Inhibition of GST tagged PERK cytoplasmic domain mediated EIF2alpha phosphorylation	ic50	0.0032	uM
1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,3-dihydroindol-1-yl]-2-(6-fluoro-2-methylindol-1-yl)ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0032	uM
N-[5-(6,7-dimethoxyquinolin-4-yl)oxy-2-pyridinyl]-1-methyl-3-oxo-2,5-diphenylpyrazole-4-carboxamide	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0040	uM
4-[2-amino-3-[5-fluoro-2-(methylamino)quinazolin-7-yl]oxy-4-methylbenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0040	uM
4-[2-amino-4-methyl-3-(2-methyl-1,3-benzothiazol-6-yl)benzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0040	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyridine-3-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0040	uM
2-amino-5-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-ethylpyridine-3-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0040	uM
6-[(2-pyrimidin-2-ylfuro[2,3-c]pyridin-3-yl)amino]naphthalen-1-ol	568039: Inhibition of pERK	ic50	0.0041	uM
1-[5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,3-dihydroindol-1-yl]-2-(1H-indol-3-yl)ethanone	1177121: Inhibition of recombinant GST-tagged PERK (unknown origin) by LanthaScreen assay	ic50	0.0050	uM
4-[4-chloro-3-[2-(methylamino)quinazolin-7-yl]oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0050	uM
4-[2-amino-4-methyl-3-(2-methylquinazolin-7-yl)oxybenzoyl]-1-methyl-2,5-diphenylpyrazol-3-one	1196988: Inhibition of human N-terminal His-tagged PERK expressed in Escherichia coli using AviTag C-terminal, N-terminal His-tagged eIF2alpha (3 to 315) as substrate by LanthaScreen TR-FRET assay	ic50	0.0050	uM
3-amino-6-[4-[[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-2-methylphenyl]-N-propan-2-ylpyrazine-2-carboxamide	1763227: Inhibition of human His-tagged PERK expressed in Escherichia coli assessed as eIF2alpha phosphorylation by TR-FRET assay	ic50	0.0050	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Thapsigargin	decreases reaction, increases phosphorylation, increases reaction, increases expression	12
4-phenylbutyric acid	decreases reaction, increases phosphorylation, increases expression, decreases expression	11
Acetylcysteine	affects cotreatment, decreases reaction, increases phosphorylation, increases expression, increases abundance (+1 more)	10
Tunicamycin	decreases reaction, increases phosphorylation, increases reaction, affects cotreatment, increases expression	8
bisphenol A	affects expression, affects cotreatment, decreases methylation, increases expression, decreases reaction (+1 more)	5
7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine	decreases phosphorylation, affects cotreatment, increases expression, increases reaction, decreases reaction (+3 more)	5
Cyclosporine	affects reaction, increases expression	5
sodium arsenite	decreases reaction, increases phosphorylation, increases abundance, increases expression, increases reaction (+1 more)	4
ochratoxin A	increases expression, increases phosphorylation, decreases reaction, decreases expression	4
Bortezomib	increases phosphorylation, increases reaction, decreases reaction, decreases response to substance	4
Tobacco Smoke Pollution	decreases reaction, increases expression, increases phosphorylation	4
Cadmium Chloride	increases phosphorylation, decreases reaction, increases expression, increases abundance	4
Resveratrol	affects cotreatment, increases expression, decreases reaction, increases phosphorylation	3
Cadmium	decreases reaction, increases abundance, increases expression, increases phosphorylation	3
Cisplatin	increases reaction, decreases response to substance, decreases reaction, increases phosphorylation, affects cotreatment (+1 more)	3
Glucose	decreases reaction, increases phosphorylation, affects cotreatment	3
Methamphetamine	affects reaction, increases phosphorylation, increases cleavage, increases expression, decreases reaction	3
Plant Extracts	affects cotreatment, increases expression, decreases expression, decreases phosphorylation	3
Rotenone	increases expression, affects reaction, increases phosphorylation, decreases reaction	3
Valproic Acid	affects cotreatment, increases expression	3
Particulate Matter	decreases reaction, increases phosphorylation, decreases expression, increases abundance	3
scutebarbatine A	increases expression	2
triphenyl phosphate	affects expression, affects reaction, increases expression	2
methylselenic acid	decreases reaction, increases phosphorylation, increases activity	2
titanium dioxide	affects expression, increases expression, increases phosphorylation	2
perhexiline maleate	decreases reaction, increases abundance, increases expression	2
hydroquinone	increases phosphorylation, decreases reaction, increases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	2
bisphenol S	decreases reaction, increases phosphorylation, increases expression	2
Sorafenib	affects binding, affects cotreatment, increases reaction, increases cleavage, increases expression (+1 more)	2

ChEMBL screening assays

153 unique, capped per target: 151 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037131	Binding	Residual activity of EIF2AK3 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem
CHEMBL1614023	Functional	PUBCHEM_BIOASSAY: Dose response cell-based high-throughput screening assay to measure PERK inhibition. (Class of assay: confirmatory) [Related pubchem assays: 1416 ]	PubChem BioAssay data set

Cellosaurus cell lines

13 cell lines: 12 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B6AQ	HepaRG PERK KO	Cancer cell line	Female
CVCL_B8F7	Abcam HCT 116 EIF2AK3 KO	Cancer cell line	Male
CVCL_B9HF	Abcam A-549 EIF2AK3 KO	Cancer cell line	Male
CVCL_D2EZ	Abcam MCF-7 EIF2AK3 KO	Cancer cell line	Female
CVCL_D9E7	Ubigene HEK293 EIF2AK3 KO	Transformed cell line	Female
CVCL_E0CI	Ubigene HeLa EIF2AK3 KO	Cancer cell line	Female
CVCL_E1NQ	HAP1 EIF2AK1 (-) EIF2AK3 (-) 1	Cancer cell line	Male
CVCL_E1NR	HAP1 EIF2AK1 (-) EIF2AK3 (-) 2	Cancer cell line	Male
CVCL_E1NV	HAP1 EIF2AK3 (-) EIF2AK4 (-) 1	Cancer cell line	Male
CVCL_E1NW	HAP1 EIF2AK3 (-) EIF2AK4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00811785	PHASE3	COMPLETED	Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT06976658	PHASE2	RECRUITING	Glucokinase Activator in Monogenic Diabetes
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT01795144	PHASE1	COMPLETED	Incretin Regulation of Insulin Secretion in Monogenic Diabetes
NCT03988764	Not specified	RECRUITING	Monogenic Diabetes Misdiagnosed as Type 1
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function