ERN1

Summary

ERN1 (endoplasmic reticulum to nucleus signaling 1, HGNC:3449) is a protein-coding gene on chromosome 17q23.3, encoding Serine/threonine-protein kinase/endoribonuclease IRE1 (O75460). Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR).

This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1.

Source: NCBI Gene 2081 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 141 total
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3449
Approved symbol	ERN1
Name	endoplasmic reticulum to nucleus signaling 1
Location	17q23.3
Locus type	gene with protein product
Status	Approved
Aliases	IRE1, IRE1P
Ensembl gene	ENSG00000178607
Ensembl biotype	protein_coding
OMIM	604033
Entrez	2081

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000433197, ENST00000577567, ENST00000579249, ENST00000583077, ENST00000583896, ENST00000584041, ENST00000606895, ENST00000680433, ENST00000680493, ENST00000680625

RefSeq mRNA: 1 — MANE Select: NM_001433 NM_001433

CCDS: CCDS45762

Canonical transcript exons

ENST00000433197 — 22 exons

Exon	Start	End
ENSE00000742412	64044860	64044927
ENSE00000742413	64045359	64045482
ENSE00000742414	64047858	64047985
ENSE00000742415	64049055	64049202
ENSE00000742416	64052780	64052979
ENSE00000742417	64053272	64053371
ENSE00000742418	64054250	64054439
ENSE00000742419	64054738	64054828
ENSE00000742421	64055675	64055948
ENSE00000742422	64057802	64057993
ENSE00000742423	64060469	64060587
ENSE00000742426	64066671	64066932
ENSE00000742427	64068190	64068291
ENSE00002687847	64039142	64044200
ENSE00002695232	64129976	64130144
ENSE00003474262	64063986	64064151
ENSE00003518071	64075175	64075247
ENSE00003586828	64079662	64079734
ENSE00003592013	64065209	64065287
ENSE00003626149	64071981	64072103
ENSE00003680883	64080775	64080808
ENSE00003685371	64098121	64098241

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 95.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6111 / max 799.4234, expressed in 1786 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167553	13.9470	1634
167555	2.4782	354
167551	2.4600	1180
167552	0.5415	296
167554	0.4304	237
167548	0.3342	75
167549	0.2802	67
167556	0.1398	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	95.03	gold quality
adrenal tissue	UBERON:0018303	94.57	gold quality
decidua	UBERON:0002450	94.56	gold quality
amniotic fluid	UBERON:0000173	94.19	gold quality
secondary oocyte	CL:0000655	93.42	gold quality
right adrenal gland cortex	UBERON:0035827	92.51	gold quality
seminal vesicle	UBERON:0000998	92.09	gold quality
right adrenal gland	UBERON:0001233	92.06	gold quality
adrenal cortex	UBERON:0001235	91.74	gold quality
adrenal gland	UBERON:0002369	91.42	gold quality
left adrenal gland cortex	UBERON:0035825	91.40	gold quality
body of pancreas	UBERON:0001150	91.38	gold quality
oocyte	CL:0000023	90.99	gold quality
left adrenal gland	UBERON:0001234	90.81	gold quality
caput epididymis	UBERON:0004358	90.65	gold quality
germinal epithelium of ovary	UBERON:0001304	90.61	gold quality
endocervix	UBERON:0000458	89.66	gold quality
endothelial cell	CL:0000115	89.45	silver quality
blood	UBERON:0000178	89.05	gold quality
sperm	CL:0000019	88.50	gold quality
lower lobe of lung	UBERON:0008949	88.27	gold quality
visceral pleura	UBERON:0002401	87.50	gold quality
corpus epididymis	UBERON:0004359	87.50	gold quality
pancreas	UBERON:0001264	87.16	gold quality
colonic epithelium	UBERON:0000397	87.11	gold quality
male germ cell	CL:0000015	86.52	gold quality
pleura	UBERON:0000977	86.43	gold quality
granulocyte	CL:0000094	86.23	gold quality
right lobe of liver	UBERON:0001114	86.20	gold quality
jejunal mucosa	UBERON:0000399	86.14	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	40.14
E-CURD-46	yes	34.81
E-CURD-122	yes	25.49
E-MTAB-8142	yes	18.16
E-ANND-3	yes	13.49
E-MTAB-9067	yes	12.33
E-HCAD-1	yes	12.29
E-HCAD-10	yes	8.19
E-MTAB-6678	yes	4.70
E-CURD-89	no	454.06

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
OS9	Activation

Upstream regulators (CollecTRI, top): ESR1, JUNB, XBP1

miRNA regulators (miRDB)

37 targeting ERN1, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-3121-5P	97.30	66.62	1146
HSA-MIR-6860	97.21	66.31	1656

Literature-anchored findings (GeneRIF, showing 40)

• examination of luminal N-terminal ligand-independent dimerization domain (PMID:11897784)
• HSP90 associates with the cytoplasmic domain of IRE1alpha (PMID:12446770)
• the N-terminal luminal domain of IRE1 alpha has at least two distinct types of interactions mediating dimerization and function in signaling (PMID:12637535)
• ATF6 and Ire1p signaling do not define the magnitude of UPR-dependent mRNA increases, even though they may be necessary for gene activation. (PMID:15063770)
• JAB1 may act as a key molecule in selecting the unfolded protein response or cell death by association and dissociation with IRE1alpha (PMID:15234121)
• hepatitis B virus S promoter responds to a novel, cell type-restricted transcriptional pathway downstream of IRE1-alpha and XBP1 (PMID:16107700)
• These results suggest that IRE1alpha-mediated mRNA cleavage functions even in mammals as a common system to regulate gene expression. (PMID:17585877)
• IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo (PMID:17638880)
• study found IRE1 attenuated by ER stress; when IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between duration of unfolded protein response branch signaling & life or death cell fate after ER stress (PMID:17991856)
• ER stress increases MTHFR expression and IRE1 and c-Jun mediate this activation (PMID:18065414)
• RNase domain of IRE1 determines the functional specificities of each of these isoforms. (PMID:18242182)
• Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the IRE1 (PMID:18840095)
• USP14 interacted with the cytoplasmic region of IRE1alpha, and the endogenous interaction between USP14 and IRE1alpha was inhibited by ER stress. (PMID:19135427)
• Transcriptional and posttranscriptional mechanisms involving NR2F1 and IRE1beta ensure low microsomal triglyceride transfer protein expression in undifferentiated intestinal cells and avoid apolipoprotein B lipoprotein biosynthesis. (PMID:20007910)
• Data conclude that IRE1alpha activity controls a subset of the ER stress response and mediates proliferation through tight control of Xbp-1 splicing. (PMID:20013084)
• Findings demonstrate that RACK1 functions as a key component in regulating the IRE1alpha signaling pathway in pancreatic beta cells. (PMID:20103773)
• IRE1-alpha-dependent phospho-CREB signaling pathway responsive to NO/Ca(2+) may play an important role in regulating ER-related cell death in glioma (PMID:20447464)
• Binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the endoplasmic reticulum (ER) and inhibits ER stress-induced apoptosis. (PMID:20625543)
• Data show that a decreased growth rate in tumors underexpressing IRE1. (PMID:20702765)
• mammalian IRE1 oligomerizes in the endoplasmic reticulum membrane and oligomerization correlates with the onset of IRE1 phosphorylation and RNase activity. (PMID:20798350)
• Data suggest that chronic epilepsy is associated with ER stress, as well as induction of both IRE1alpha-mediated pro- and anti-apoptotic signaling pathways. (PMID:20965234)
• 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)
• REVIEW: Modulating stress responses by the UPRosome (PMID:21482118)
• endoplasmic reticulum to nucleus signaling 1 is activated following oxygen-glucose deprivation of rat cortical cells (PMID:21525936)
• Targeted and selective activation of the catalytic properties of IRE1alpha may consequently define new strategies to protect cells from deleterious effects of ER stress signaling. (PMID:21680894)
• IRE1 plays an essential role in ER stress-mediated aggregation of mutant HTT via the inhibition of autophagy flux. (PMID:21954231)
• Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway. (PMID:22194594)
• Cdc37-mediated direct interaction between Hsp90/Cdc37 and an IRE1alpha cytosolic motif is important to maintain basal IRE1alpha activity and contributes to normal protein homeostasis and unfolded protein response under physiological stimulation. (PMID:22199355)
• these findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin. (PMID:22219383)
• IRE1a-mediated induction of apoptosis and inhibition of proliferation in response to endoplasmic reticulum stress is through downregulation PLK1. (PMID:22314839)
• Inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. (PMID:22315414)
• The results of this study strongly suggested that IRE1alpha-JNK signaling is activated by chronic epilepsy. To our knowledge, this is the first report that IRE1alpha-JNK signaling is activated in MTLE patients. (PMID:22419015)
• BiP binds to IRE1 and PERK in a different manner. (PMID:22446326)
• IRE1alpha is a key regulator of SPARC expression in vitro in a glioma model. (PMID:22718352)
• IRE1/XBP1 controls the induction of autophagy/ERAD(II) during the unfolded protein response by activating the ER membrane transporter SLC33A1/AT-1 (PMID:22787145)
• one of three endoplasmic reticulum transmembrane protein sensors that signals the unfolded protein response [review] (PMID:22917505)
• IRE1alpha inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock (PMID:23001845)
• the study would provide insights into how the transmembrane domain plays a role in regulating the IRE1alpha protein activity. (PMID:23041190)
• IRE1alpha regulates translation of a proapoptotic protein, Caspase-2, through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response (PMID:23042294)
• PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1alpha-mediated unfolded protein response. (PMID:23103912)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ern1	ENSMUSG00000020715
rattus_norvegicus	Ern1	ENSRNOG00000012864

Paralogs (1): ERN2 (ENSG00000134398)

Protein

Protein identifiers

Serine/threonine-protein kinase/endoribonuclease IRE1 — O75460 (reviewed: O75460)

Alternative names: Endoplasmic reticulum-to-nucleus signaling 1, Inositol-requiring protein 1, Ire1-alpha

All UniProt accessions (3): O75460, A0A7P0TA38, A0A7P0TAB0

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP. Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity. The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA. The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes. Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A.

Subunit / interactions. Monomer. Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities. Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges. Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP. Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein. Interaction with HSPA5 also competitively inhibits ERN1 interaction with MANF. Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization. Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1. Interacts with TAOK3 and TRAF2. Interacts with RNF13. Interacts with LACC1. Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability. Interacts (via N-terminus) with P4HB/PDIA1; the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity. Interacts with TMBIM6; this interaction inhibits ERN1 activity. Interacts (via luminal domain) with MANF (via C-terminus); the interaction is decreased in the presence of increasing concentrations of Ca(2+).

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitously expressed. High levels observed in pancreatic tissue.

Post-translational modifications. Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain. In response to ER stress, phosphorylated at Ser-724, Ser-729 and possibly Ser-726; phosphorylation promotes oligomerization and endoribonuclease activity. Dephosphorylated at Ser-724, Ser-729 and possibly Ser-726 by RPAP2 to abort failed ER-stress adaptation and trigger apoptosis. Phosphorylated at Ser-724; in response to the ER stressor tunicamycin. ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities.

Activity regulation. The kinase domain is activated by trans-autophosphorylation following homodimerization. Kinase activity is required for activation of the endoribonuclease domain. Endoribonuclease activity is specifically inhibited by hydroxy-aryl-aldehydes (HAA).

Induction. Induced by the ER stressor tunicamycin.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O75460-1	1	yes
O75460-2	2

RefSeq proteins (1): NP_001424* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR010513	KEN_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018391	PQQ_b-propeller_rpt	Repeat
IPR038357	KEN_sf	Homologous_superfamily
IPR045133	IRE1/2-like	Family

Pfam: PF00069, PF06479

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (122 total): strand 38, helix 29, turn 9, sequence variant 7, mutagenesis site 7, sequence conflict 7, binding site 5, modified residue 3, region of interest 3, compositionally biased region 2, topological domain 2, splice variant 2, domain 2, signal peptide 1, chain 1, active site 1, site 1, glycosylation site 1, transmembrane region 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
6W39	X-RAY DIFFRACTION	1.74
7BMK	X-RAY DIFFRACTION	1.85
6W3K	X-RAY DIFFRACTION	2.08
6HX1	X-RAY DIFFRACTION	2.14
6URC	X-RAY DIFFRACTION	2.2
6W3C	X-RAY DIFFRACTION	2.3
6XDD	X-RAY DIFFRACTION	2.4
8UVL	X-RAY DIFFRACTION	2.43
6XDB	X-RAY DIFFRACTION	2.45
4YZ9	X-RAY DIFFRACTION	2.46
4YZC	X-RAY DIFFRACTION	2.49
4U6R	X-RAY DIFFRACTION	2.5
6XDF	X-RAY DIFFRACTION	2.54
6W3B	X-RAY DIFFRACTION	2.57
5HGI	X-RAY DIFFRACTION	2.58
4Z7G	X-RAY DIFFRACTION	2.6
9N88	ELECTRON MICROSCOPY	2.6
6W3A	X-RAY DIFFRACTION	2.61
3P23	X-RAY DIFFRACTION	2.7
6HV0	X-RAY DIFFRACTION	2.73
6W3E	X-RAY DIFFRACTION	2.74
4Z7H	X-RAY DIFFRACTION	2.9
9GOW	X-RAY DIFFRACTION	3
2HZ6	X-RAY DIFFRACTION	3.1
4YZD	X-RAY DIFFRACTION	3.1
6SHC	X-RAY DIFFRACTION	3.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75460-F1	73.50	0.39

Functional residue map

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

Catalytic / active sites (2): 688 (proton acceptor); 892 (interacts with hydroxy-aryl-aldehyde inhibitors)

Ligand- & substrate-binding residues (5): 577–585; 599; 643–645; 690–693; 711

Post-translational modifications (3): 724, 729, 973

Glycosylation sites (1): 176

Mutagenesis-validated functional residues (7):

Position	Phenotype
105	impaired ability to homodimerize.
109	no effect on dimerization. no effect on interaction with p4hb; when associated with s-148 and s-332.
123	abolishes ability to homodimerize.
125	abolishes ability to homodimerize.
148	no effect on dimerization. weakens dimer; when associated with s-332. abolishes interaction with pdia6. prolonged splici
332	no effect on dimerization. weakens dimer; when associated with s-148. no effect on interaction with p4hb; when associate
599	loss of autophosphorylation and of endoribonuclease activity. inhibition of growth arrest.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-381070	IRE1alpha activates chaperones

MSigDB gene sets: 294 (showing top): CREL_01, GOBP_REGULATION_OF_AUTOPHAGY, GOMF_ENDONUCLEASE_ACTIVITY, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, RORA1_01, GOMF_NUCLEASE_ACTIVITY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (26): endothelial cell proliferation (GO:0001935), mRNA catabolic process (GO:0006402), protein phosphorylation (GO:0006468), regulation of macroautophagy (GO:0016241), endoplasmic reticulum unfolded protein response (GO:0030968), positive regulation of RNA splicing (GO:0033120), cellular response to unfolded protein (GO:0034620), response to endoplasmic reticulum stress (GO:0034976), cellular response to vascular endothelial growth factor stimulus (GO:0035924), IRE1-mediated unfolded protein response (GO:0036498), positive regulation of JNK cascade (GO:0046330), mRNA splicing, via endonucleolytic cleavage and ligation (GO:0070054), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), cellular response to hydrogen peroxide (GO:0070301), cellular response to glucose stimulus (GO:0071333), positive regulation of endoplasmic reticulum unfolded protein response (GO:1900103), insulin metabolic process (GO:1901142), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), mRNA processing (GO:0006397), RNA catabolic process (GO:0006401), apoptotic process (GO:0006915), response to unfolded protein (GO:0006986), negative regulation of gene expression (GO:0010629), intrinsic apoptotic signaling pathway (GO:0097193), positive regulation of response to endoplasmic reticulum stress (GO:1905898)

GO Molecular Function (23): magnesium ion binding (GO:0000287), RNA endonuclease activity (GO:0004521), protein serine/threonine kinase activity (GO:0004674), platelet-derived growth factor receptor binding (GO:0005161), ATP binding (GO:0005524), hydrolase activity (GO:0016787), enzyme binding (GO:0019899), Hsp70 protein binding (GO:0030544), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ADP binding (GO:0043531), obsolete unfolded protein binding (GO:0051082), Hsp90 protein binding (GO:0051879), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), endonuclease activity (GO:0004519), RNA nuclease activity (GO:0004540), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (11): nuclear inner membrane (GO:0005637), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Ire1 complex (GO:1990332), AIP1-IRE1 complex (GO:1990597), IRE1-TRAF2-ASK1 complex (GO:1990604), IRE1-RACK1-PP2A complex (GO:1990630), membrane (GO:0016020), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Unfolded Protein Response (UPR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA metabolic process	2
response to endoplasmic reticulum stress	2
endoplasmic reticulum unfolded protein response	2
intrinsic apoptotic signaling pathway	2
protein kinase activity	2
adenyl ribonucleotide binding	2
protein binding	2
heat shock protein binding	2
nuclease activity	2
cellular anatomical structure	2
cytoplasm	2
intracellular membrane-bounded organelle	2
endoplasmic reticulum membrane	2
membrane protein complex	2
endoplasmic reticulum protein-containing complex	2
protein-containing complex	2
epithelial cell proliferation	1
RNA catabolic process	1
negative regulation of gene expression	1
phosphorylation	1
protein modification process	1
regulation of autophagy	1
macroautophagy	1
cellular response to unfolded protein	1
intracellular signal transduction	1
RNA splicing	1
positive regulation of gene expression	1
regulation of RNA splicing	1
response to unfolded protein	1
cellular response to topologically incorrect protein	1
cellular response to stress	1
cellular response to growth factor stimulus	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
RNA splicing, via endonucleolytic cleavage and ligation	1
mRNA processing	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
intracellular glucose homeostasis	1

Protein interactions and networks

STRING

3046 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERN1	HSPA5	P11021	999
ERN1	TRAF2	Q12933	993
ERN1	MAP3K5	Q99683	988
ERN1	XBP1	P17861	976
ERN1	ATF6	P18850	968
ERN1	EIF2S1	P05198	895
ERN1	TNF	P01375	892
ERN1	DDIT3	P35638	881
ERN1	EDEM1	Q92611	851
ERN1	TMBIM6	P55061	851
ERN1	ATF4	P18848	833
ERN1	ATF6B	Q99941	807
ERN1	HSP90AB1	P08238	797
ERN1	HSP90AA1	P07900	796
ERN1	BCL2	P10415	778

IntAct

58 interactions, top by confidence:

A	B	Type	Score
ERN1	TRAF2	psi-mi:“MI:0915”(physical association)	0.630
TRAF2	ERN1	psi-mi:“MI:2364”(proximity)	0.630
ERN1	ERN1	psi-mi:“MI:0915”(physical association)	0.610
ERN1	ERN1	psi-mi:“MI:0407”(direct interaction)	0.610
ERN1	YIPF5	psi-mi:“MI:0915”(physical association)	0.540
ERN1	YIPF5	psi-mi:“MI:0403”(colocalization)	0.540
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
Bax	ERN1	psi-mi:“MI:0915”(physical association)	0.520
ERN1	SYVN1	psi-mi:“MI:0915”(physical association)	0.520
ERN1	TAOK3	psi-mi:“MI:0915”(physical association)	0.510
ERN1	BAX	psi-mi:“MI:0407”(direct interaction)	0.440
SRPK2	ERN1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
	ERN1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ERN1	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
HSPA5	ERN1	psi-mi:“MI:0915”(physical association)	0.400
Bak1	ERN1	psi-mi:“MI:0915”(physical association)	0.400
Hspa5	ERN1	psi-mi:“MI:0915”(physical association)	0.400
UBC	ERN1	psi-mi:“MI:0915”(physical association)	0.400
ERN1	SEC24D	psi-mi:“MI:0914”(association)	0.350

BioGRID (108): STUB1 (Affinity Capture-MS), OTUB1 (Affinity Capture-MS), UCHL1 (Affinity Capture-MS), FBXL21 (Affinity Capture-MS), FBXO11 (Affinity Capture-MS), STUB1 (Affinity Capture-Western), ERN1 (Reconstituted Complex), ERN1 (Biochemical Activity), TRAF2 (Affinity Capture-Western), ERN1 (Synthetic Lethality), ERN1 (Co-localization), ERN1 (Co-localization), TRAF2 (Affinity Capture-Western), MAP3K5 (Affinity Capture-Western), SYVN1 (Affinity Capture-Western)

ESM2 similar proteins: A0A072VIM5, A0A0K0PU92, A0JM23, A2CIR7, F4IG73, F4JD14, G3LSH3, G8GTN7, O00750, O42132, O75460, O80560, P03372, P0CI65, P50241, P50242, P57717, P57753, Q0JJ01, Q29040, Q2HW56, Q2QXZ2, Q2RAQ5, Q53AD2, Q5D0W8, Q5M9H0, Q5YLM1, Q5ZLG9, Q6AZT7, Q6KAE5, Q6NLQ8, Q6PJI9, Q6WQJ1, Q7EZ44, Q7T0L6, Q7TNH6, Q7XAP4, Q7Z494, Q8C0M0, Q8CFE5

Diamond homologs: A0A2R6XIK6, A7A1P0, B4J3F1, B4KYX8, B4LDJ6, B5VNQ3, C0LGJ1, F4HQ17, G0RBE3, O08875, O15075, O59854, O61267, O75460, O93982, O94537, P08414, P0C431, P0C8M8, P13186, P16912, P23561, P28583, P28829, P30290, P32361, P32485, P34101, P43450, P45984, P49186, P49187, P53779, P97377, Q00534, Q01389, Q07250, Q09170, Q09499, Q09892

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
“ER stress”	up-regulates	ERN1
ERN1	up-regulates	JUN
DAB2IP	“up-regulates activity”	ERN1	binding
Unfolded_Proteins	up-regulates	ERN1
HSPA5	“down-regulates activity”	ERN1	binding
ERN1	“down-regulates activity”	JNK
ERN1	“up-regulates quantity by expression”	XBP1	“post transcriptional regulation”
ERN1	“up-regulates quantity by expression”	OS9	“transcriptional regulation”
PPM1L	“up-regulates activity”	ERN1	dephosphorylation
MARCHF5	“down-regulates activity”	ERN1	ubiquitination
MAP3K5	“up-regulates activity”	ERN1	phosphorylation
ERN1	“up-regulates activity”	XBP1	phosphorylation
PDIA6	“down-regulates activity”	ERN1
SOD1	“up-regulates activity”	ERN1	binding
ERN1	“up-regulates activity”	TRAF2	binding
E	“down-regulates activity”	ERN1
ERN1	“up-regulates activity”	ERN1	phosphorylation
P4HB	“down-regulates activity”	ERN1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3646 predictions. Top by Δscore:

Variant	Effect	Δscore
17:64044201:C:CC	acceptor_gain	1.0000
17:64044854:GCTTA:G	donor_loss	1.0000
17:64044855:CTTAC:C	donor_loss	1.0000
17:64044856:TTACC:T	donor_loss	1.0000
17:64044857:TACCT:T	donor_loss	1.0000
17:64044858:A:T	donor_loss	1.0000
17:64044859:C:CA	donor_loss	1.0000
17:64044923:CAGGT:C	acceptor_gain	1.0000
17:64044925:GGTC:G	acceptor_loss	1.0000
17:64044927:TC:T	acceptor_loss	1.0000
17:64044928:C:CA	acceptor_loss	1.0000
17:64044928:C:CC	acceptor_gain	1.0000
17:64044929:T:C	acceptor_loss	1.0000
17:64045478:ACGTC:A	acceptor_gain	1.0000
17:64045479:CGTC:C	acceptor_gain	1.0000
17:64045479:CGTCC:C	acceptor_gain	1.0000
17:64045481:TC:T	acceptor_gain	1.0000
17:64045481:TCCTG:T	acceptor_loss	1.0000
17:64045482:CC:C	acceptor_gain	1.0000
17:64045483:C:CA	acceptor_loss	1.0000
17:64045483:C:CC	acceptor_gain	1.0000
17:64045484:T:G	acceptor_loss	1.0000
17:64047856:ACCTG:A	donor_loss	1.0000
17:64047857:CC:C	donor_loss	1.0000
17:64047981:GTCTT:G	acceptor_gain	1.0000
17:64047983:CTT:C	acceptor_gain	1.0000
17:64047984:TT:T	acceptor_gain	1.0000
17:64047986:C:CC	acceptor_gain	1.0000
17:64047988:A:AC	acceptor_gain	1.0000
17:64047988:A:C	acceptor_gain	1.0000

AlphaMissense

6405 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:64044860:C:A	K907N	1.000
17:64044860:C:G	K907N	1.000
17:64044863:A:C	N906K	1.000
17:64044863:A:T	N906K	1.000
17:64044912:C:A	R890M	1.000
17:64044914:G:C	F889L	1.000
17:64044914:G:T	F889L	1.000
17:64044916:A:G	F889L	1.000
17:64045392:A:G	W874R	1.000
17:64045392:A:T	W874R	1.000
17:64045474:G:C	S846R	1.000
17:64045474:G:T	S846R	1.000
17:64045476:T:G	S846R	1.000
17:64052822:C:A	W737C	1.000
17:64052822:C:G	W737C	1.000
17:64052824:A:G	W737R	1.000
17:64052824:A:T	W737R	1.000
17:64052885:C:A	K716N	1.000
17:64052885:C:G	K716N	1.000
17:64052900:G:C	D711E	1.000
17:64052900:G:T	D711E	1.000
17:64052901:T:A	D711V	1.000
17:64052901:T:C	D711G	1.000
17:64052901:T:G	D711A	1.000
17:64052949:A:G	L695P	1.000
17:64052970:T:A	D688V	1.000
17:64052970:T:C	D688G	1.000
17:64052970:T:G	D688A	1.000
17:64052973:C:A	R687I	1.000
17:64054281:G:T	A641D	1.000

dbSNP variants (sampled 300 via entrez): RS1000049197 (17:64119874 G>A), RS1000064677 (17:64093111 C>A,T), RS1000183534 (17:64126195 C>G), RS1000214926 (17:64091952 ACC>A), RS1000291050 (17:64073522 C>T), RS1000304430 (17:64116982 T>G), RS1000326637 (17:64076390 A>C), RS1000362287 (17:64070543 A>C,G), RS1000404892 (17:64054625 C>A,T), RS1000470295 (17:64097909 G>A,C,T), RS1000521973 (17:64075287 G>A,C), RS1000527358 (17:64115822 T>A), RS1000534528 (17:64099485 G>A,C), RS1000560786 (17:64085898 C>T), RS1000570070 (17:64104089 T>A,C)

Disease associations

OMIM: gene MIM:604033 | 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
GCST004261_1	Liver injury in anti-retroviral drug treated HIV	2.000000e-06
GCST005537_36	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	8.000000e-10
GCST90013406_178	Liver enzyme levels (alkaline phosphatase)	3.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163101 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 150,749 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL1950289	TANZISERTIB	2	419
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL574737	UCN-01	2	2,217
CHEMBL1908397	KW-2449	1	622
CHEMBL3545360	ASP-3026	1	665
CHEMBL4289017	PF-03814735	1	537
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — IRE family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 34 [PMID: 24749861]	Inhibition	7.33	pIC50

Binding affinities (BindingDB)

285 measured of 764 human assays (1039 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-hydroxy-6-[5-(4-methylpiperazine-1-carbonyl)thiophen-2-yl]naphthalene-1-carbaldehyde	IC50	5 nM	US-9241942: IRE-1α inhibitors
CERITINIB	IC50	5 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
N-benzyl-3-(3-formyl-4-hydroxy-5-methoxyphenyl)benzamide	IC50	6 nM	US-9241942: IRE-1α inhibitors
2-chloro-N-[5-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]naphthalen-1-yl]benzenesulfonamide	IC50	10 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
US8614253, 38-7	IC50	15 nM	US-8614253: IRE-1α inhibitors
N-cyclohexyl-3-(3-formyl-4-hydroxy-5-methoxyphenyl)benzamide	IC50	19 nM	US-9241942: IRE-1α inhibitors
methyl 4-(3-formyl-4-hydroxy-5-nitrophenyl)benzoate	IC50	21 nM	US-9241942: IRE-1α inhibitors
BDBM50242742	IC50	21.9 nM	US-10913744: LRRK2 inhibitors and methods of making and using the same
2-hydroxy-3-methoxy-5-thiophen-2-ylbenzaldehyde	IC50	22 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-6-pyridin-3-ylnaphthalene-1-carbaldehyde	IC50	23 nM	US-9241942: IRE-1α inhibitors
US8614253, 38-6	IC50	23 nM	US-8614253: IRE-1α inhibitors
3-(5-formyl-6-hydroxynaphthalen-2-yl)benzamide	IC50	26 nM	US-9241942: IRE-1α inhibitors
2,3-dibromo-6-hydroxy-5-methoxybenzaldehyde	IC50	30 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-3-nitro-5-thiophen-2-ylbenzaldehyde	IC50	30 nM	US-9241942: IRE-1α inhibitors
3-(3-formyl-4-hydroxy-5-nitrophenyl)benzamide	IC50	32 nM	US-9241942: IRE-1α inhibitors
3-fluoro-2-hydroxy-5-thiophen-2-ylbenzaldehyde	IC50	34 nM	US-9241942: IRE-1α inhibitors
US8614253, 38-5	IC50	34 nM	US-8614253: IRE-1α inhibitors
4-(5-formyl-6-hydroxynaphthalen-2-yl)-N,N-dimethylbenzamide	IC50	36 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-3-methoxy-5-pyrimidin-5-ylbenzaldehyde	IC50	39 nM	US-9241942: IRE-1α inhibitors
3-(3-fluoro-5-formyl-4-hydroxyphenyl)-N-[(4-methoxyphenyl)methyl]benzamide	IC50	40 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-3-nitro-5-thiophen-2-ylbenzaldehyde	IC50	42 nM	US-9241942: IRE-1α inhibitors
3-hydroxyquinoline-4-carbaldehyde	IC50	45 nM	US-9241942: IRE-1α inhibitors
5-(5-acetylthiophen-2-yl)-3-fluoro-2-hydroxybenzaldehyde	IC50	46 nM	US-9241942: IRE-1α inhibitors
3-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide	IC50	46 nM	US-9241942: IRE-1α inhibitors
4-bromo-3-formyl-2-hydroxybenzamide	IC50	47 nM	US-9241942: IRE-1α inhibitors
5-(furan-2-yl)-2-hydroxy-3-methoxybenzaldehyde	IC50	51 nM	US-9241942: IRE-1α inhibitors
N-[(2-chlorophenyl)methyl]-4-methyl-3-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]benzamide	IC50	52 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-chloro-N-[4-[[2-methyl-5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]naphthalen-1-yl]benzenesulfonamide	IC50	63 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
3-(3-formyl-4-hydroxyphenyl)-N-(2-piperidin-1-ylethyl)benzamide	IC50	66 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-6-pyrimidin-5-ylnaphthalene-1-carbaldehyde	IC50	66 nM	US-9241942: IRE-1α inhibitors
AP26113	IC50	66 nM
2-hydroxy-6-[4-(morpholine-4-carbonyl)phenyl]naphthalene-1-carbaldehyde	IC50	67 nM	US-9241942: IRE-1α inhibitors
3-fluoro-2-hydroxy-5-pyrimidin-5-ylbenzaldehyde	IC50	70 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-3-methoxy-5-(6-methoxy-3-pyridinyl)benzaldehyde	IC50	74 nM	US-9241942: IRE-1α inhibitors
3-fluoro-2-hydroxy-5-thiophen-3-ylbenzaldehyde	IC50	74 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-6-[3-(morpholine-4-carbonyl)phenyl]naphthalene-1-carbaldehyde	IC50	74 nM	US-9241942: IRE-1α inhibitors
3-(5-formyl-6-hydroxynaphthalen-2-yl)benzoic acid	IC50	79 nM	US-9241942: IRE-1α inhibitors
6-bromo-2-hydroxy-3-methoxybenzaldehyde	IC50	80 nM	US-9241942: IRE-1α inhibitors
5-(furan-3-yl)-2-hydroxy-3-nitrobenzaldehyde	IC50	81 nM	US-9241942: IRE-1α inhibitors
5-(1-benzofuran-2-yl)-2-hydroxy-3-methoxybenzaldehyde	IC50	82 nM	US-9241942: IRE-1α inhibitors
4-(3-formyl-4-hydroxy-5-methoxyphenyl)benzamide	IC50	82 nM	US-9241942: IRE-1α inhibitors
3-(3-formyl-4-hydroxyphenyl)-N-(2-morpholin-4-ylethyl)benzamide	IC50	84 nM	US-9241942: IRE-1α inhibitors
4-(3-fluoro-5-formyl-4-hydroxyphenyl)benzamide	IC50	85 nM	US-9241942: IRE-1α inhibitors
3-fluoro-5-(furan-3-yl)-2-hydroxybenzaldehyde	IC50	88 nM	US-9241942: IRE-1α inhibitors
3-(3-formyl-4-hydroxy-5-nitrophenyl)-N-propylbenzamide	IC50	94 nM	US-9241942: IRE-1α inhibitors
5-(5-acetylthiophen-2-yl)-2-hydroxy-3-methoxybenzaldehyde	IC50	97 nM	US-9241942: IRE-1α inhibitors
2-chloro-N-[6-methyl-5-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxynaphthalen-1-yl]benzenesulfonamide	IC50	98 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-hydroxy-5-thiophen-2-ylbenzaldehyde	IC50	100 nM	US-9241942: IRE-1α inhibitors
2-hydroxy-5-isoquinolin-4-yl-3-methoxybenzaldehyde	IC50	100 nM	US-9241942: IRE-1α inhibitors
3-(3-formyl-4-hydroxyphenyl)-N-propylbenzamide	IC50	100 nM	US-9241942: IRE-1α inhibitors

ChEMBL bioactivities

1450 potent at pChembl≥5 of 1813 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.30	IC50	0.05	nM	CHEMBL4757194
10.10	IC50	0.08	nM	CHEMBL4777304
10.05	IC50	0.09	nM	CHEMBL4789787
10.00	IC50	0.1	nM	CHEMBL4798215
10.00	IC50	0.1	nM	CHEMBL4748828
9.96	IC50	0.11	nM	CHEMBL4790916
9.59	IC50	0.26	nM	CHEMBL5557870
9.57	IC50	0.27	nM	CHEMBL5565861
9.54	IC50	0.29	nM	CHEMBL5563969
9.54	IC50	0.29	nM	CHEMBL5561734
9.46	IC50	0.35	nM	CHEMBL5555999
9.42	IC50	0.38	nM	CHEMBL5557276
9.41	IC50	0.39	nM	CHEMBL5558833
9.32	IC50	0.48	nM	CHEMBL3356009
9.23	IC50	0.59	nM	CHEMBL5562014
9.18	IC50	0.66	nM	CHEMBL5542252
9.11	IC50	0.78	nM	CHEMBL5532412
9.07	IC50	0.85	nM	CHEMBL3356007
9.01	IC50	0.98	nM	CHEMBL5555815
9.00	IC50	1	nM	CHEMBL5825356
9.00	IC50	1	nM	CHEMBL5860590
9.00	IC50	1	nM	CHEMBL6035111
9.00	IC50	1	nM	CHEMBL6004827
9.00	IC50	1	nM	CHEMBL5915913
9.00	IC50	1	nM	CHEMBL5877422
9.00	IC50	1	nM	CHEMBL5887322
9.00	IC50	1	nM	CHEMBL5931480
9.00	IC50	1	nM	CHEMBL5847838
9.00	IC50	1	nM	CHEMBL5806781
8.96	IC50	1.1	nM	CHEMBL5560090
8.74	IC50	1.8	nM	CHEMBL5557507
8.74	IC50	1.8	nM	CHEMBL5523599
8.70	IC50	2	nM	CHEMBL5567735
8.70	IC50	2	nM	CHEMBL5906730
8.70	IC50	2	nM	CHEMBL5851394
8.70	IC50	2	nM	CHEMBL6005564
8.70	IC50	2	nM	CHEMBL5848563
8.70	IC50	2	nM	CHEMBL5767361
8.70	IC50	2	nM	CHEMBL5998758
8.70	IC50	2	nM	CHEMBL5977527
8.70	IC50	2	nM	CHEMBL5984317
8.70	IC50	2	nM	CHEMBL6052655
8.70	IC50	2	nM	CHEMBL5989440
8.68	IC50	2.1	nM	CHEMBL5558833
8.68	IC50	2.1	nM	CHEMBL5555363
8.68	IC50	2.1	nM	CHEMBL5556840
8.66	IC50	2.2	nM	CHEMBL5542651
8.54	IC50	2.9	nM	CHEMBL5555815
8.52	IC50	3	nM	CHEMBL3665053
8.52	IC50	3	nM	CHEMBL5786892

PubChem BioAssay actives

344 with measured affinity, of 840 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-(4-cyanophenyl)-N-[2-fluoro-4-[2-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]-7-oxo-8-propan-2-ylpteridin-6-yl]phenyl]methanesulfonamide	1678538: Inhibition of human His-tagged IRE1alpha expressed in Sf9 insect cells preincubated for 1 hr followed by Alexa fluor 647-labeled probe addition and measured after 1 hr by TR-FRET assay	ic50	0.0001	uM
N-[4-[2-[[4-(dimethylamino)cyclohexyl]amino]-7-oxo-8-propan-2-ylpteridin-6-yl]-2,6-difluorophenyl]-1-[1-(trifluoromethyl)cyclopropyl]methanesulfonamide	1678538: Inhibition of human His-tagged IRE1alpha expressed in Sf9 insect cells preincubated for 1 hr followed by Alexa fluor 647-labeled probe addition and measured after 1 hr by TR-FRET assay	ic50	0.0001	uM
1-(2-cyano-4-methylphenyl)-N-[2-fluoro-4-[2-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]-7-oxo-8-propan-2-ylpteridin-6-yl]phenyl]methanesulfonamide	1678538: Inhibition of human His-tagged IRE1alpha expressed in Sf9 insect cells preincubated for 1 hr followed by Alexa fluor 647-labeled probe addition and measured after 1 hr by TR-FRET assay	ic50	0.0001	uM
1-(3-methoxyphenyl)-N-[2,3,6-trifluoro-4-[2-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]-7-oxo-8-propan-2-ylpyrido[2,3-d]pyrimidin-6-yl]phenyl]methanesulfonamide	1678538: Inhibition of human His-tagged IRE1alpha expressed in Sf9 insect cells preincubated for 1 hr followed by Alexa fluor 647-labeled probe addition and measured after 1 hr by TR-FRET assay	ic50	0.0001	uM
N-[2-fluoro-4-[2-[[4-[2-methoxyethyl(methyl)amino]cyclohexyl]amino]-7-oxo-8-propan-2-ylpyrido[2,3-d]pyrimidin-6-yl]phenyl]-1-(4-fluorophenyl)methanesulfonamide	1678538: Inhibition of human His-tagged IRE1alpha expressed in Sf9 insect cells preincubated for 1 hr followed by Alexa fluor 647-labeled probe addition and measured after 1 hr by TR-FRET assay	ic50	0.0001	uM
N-[4-[2-[[4-(dimethylamino)cyclohexyl]amino]-7-oxo-8-propan-2-ylpyrido[2,3-d]pyrimidin-6-yl]-3,5-difluorophenyl]-1-(4-fluorophenyl)methanesulfonamide	1678538: Inhibition of human His-tagged IRE1alpha expressed in Sf9 insect cells preincubated for 1 hr followed by Alexa fluor 647-labeled probe addition and measured after 1 hr by TR-FRET assay	ic50	0.0001	uM
N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0003	uM
N-[2,6-difluoro-3-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0003	uM
N-[2,3-difluoro-6-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0003	uM
1-phenyl-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0003	uM
1-phenyl-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5R)-5-(fluoromethyl)piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0003	uM
N-[3-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0004	uM
3,3,3-trifluoro-N-[2-fluoro-6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]propane-1-sulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0004	uM
2-chloro-N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]benzenesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0005	uM
1-phenyl-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-fluoro-5-methylpiperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0006	uM
N-[2,6-dimethyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-3,3,3-trifluoropropane-1-sulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0007	uM
1-phenyl-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5S)-5-(fluoromethyl)piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0008	uM
N-[4-[[3-[2-[(4-aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridinyl]oxy]-3-methylnaphthalen-1-yl]-2-chlorobenzenesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0008	uM
N-[2,3-difluoro-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0010	uM
3,3,3-trifluoro-N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]propane-1-sulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0011	uM
2-cyclopropyl-N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]ethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0018	uM
N-[2-fluoro-3-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0018	uM
1-phenyl-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S,5R)-5-fluoropiperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0020	uM
N-[2-fluoro-5-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0021	uM
1-cyclohexyl-N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0021	uM
N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]cyclohexanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0022	uM
1-phenyl-N-[2,3,6-trifluoro-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]methanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0031	uM
N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]cyclopentanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0033	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148336: Binding affinity to human ERN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0043	uM
N-[6-methyl-5-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]propane-1-sulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0047	uM
2-hydroxy-6-[5-(4-methylpiperazine-1-carbonyl)thiophen-2-yl]naphthalene-1-carbaldehyde	1755532: Inhibition of IRE1 in human RPMI 8226 cells assessed as reduction in XBP1 splicing incubated for 3 hrs by RT-PCR method	ic50	0.0050	uM
N-[3-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-1H-benzimidazol-2-amine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0051	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507941: Binding affinity to ERN1	kd	0.0057	uM
4-N-[4-[2-[4-(1H-benzimidazol-2-ylamino)-2-methylnaphthalen-1-yl]oxy-3-pyridinyl]pyrimidin-2-yl]cyclohexane-1,4-diamine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0064	uM
N-[4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-1H-benzimidazol-2-amine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0097	uM
4-N-[4-[2-[4-(1H-benzimidazol-2-ylamino)naphthalen-1-yl]oxy-3-pyridinyl]pyrimidin-2-yl]cyclohexane-1,4-diamine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0110	uM
N-[4-[[3-[2-[(4-aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridinyl]oxy]-3-methylnaphthalen-1-yl]-2-cyanobenzenesulfonamide	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0120	uM
N-[4-[2-[4-(1H-benzimidazol-2-ylamino)-2-methylnaphthalen-1-yl]oxy-3-pyridinyl]pyrimidin-2-yl]-N’,N’-dimethylethane-1,2-diamine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0140	uM
4-N-[4-[2-[4-(1,3-benzoxazol-2-ylamino)-2-methylnaphthalen-1-yl]oxy-3-pyridinyl]pyrimidin-2-yl]cyclohexane-1,4-diamine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0140	uM
2-chloro-N-[5-[[3-[2-[[(3S)-5,5-difluoropiperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]-6-methylnaphthalen-1-yl]benzenesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0170	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	1424997: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0190	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624835: Binding constant for ERN1 kinase domain	kd	0.0210	uM
N-[5-[[3-[2-[(4-aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridinyl]oxy]-6-methylnaphthalen-1-yl]-2-chlorobenzenesulfonamide	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0220	uM
4-[(4-aminocyclohexyl)amino]-N-[6-chloro-3-[(2-chlorophenyl)sulfonylamino]-2-fluorophenyl]thieno[3,2-d]pyrimidine-7-carboxamide	1678649: Competitive inhibition of IRE1alpha LKR domain (Q470 to L997 residues) (unknown origin) expressed in Sf9 insect cells using mini-XBP-1 stem-loop RNA as substrate and measured every 2 mins for 50 mins by FRET assay	ic50	0.0220	uM
4-[(4-aminocyclohexyl)amino]-N-[6-chloro-3-[(2,5-difluorophenyl)sulfonylamino]-2-fluorophenyl]thieno[3,2-d]pyrimidine-7-carboxamide	1678649: Competitive inhibition of IRE1alpha LKR domain (Q470 to L997 residues) (unknown origin) expressed in Sf9 insect cells using mini-XBP-1 stem-loop RNA as substrate and measured every 2 mins for 50 mins by FRET assay	ic50	0.0240	uM
N-[4-[[6-chloro-3-(1H-indazol-5-yl)imidazo[1,2-b]pyridazin-8-yl]amino]cyclohexyl]-2-morpholin-4-ylacetamide	1602747: Inhibition of dephosphorylated IRE1alpha (G547 to L977 residues) (unknown origin) -dependent cleavage of FAM-labeled stem-loop RNA containing the XBP1 cleavage site preincubated for 30 mins followed by RNA XBP1 substrate addition and measured after 15 mins by FRET assay	ic50	0.0270	uM
N-[4-[[3-[2-[(1-methylpiperidin-3-yl)amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-1H-benzimidazol-2-amine	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0290	uM
N-[3-methyl-4-[[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-2-pyridinyl]oxy]phenyl]-1-phenylmethanesulfonamide	2076750: Inhibition of His-tagged IRE1alpha (G547 to L977 residues) (unknown origin) expressed in Sf9 cells preincubated with anti-His Europium labeled antibody for 1 hr prior to compound addition followed by tracer 236 addition and measured after 1 hr by TR-FRET assay	ic50	0.0290	uM
4-[(4-aminocyclohexyl)amino]-N-[3-(benzylsulfonylamino)-6-chloro-2-fluorophenyl]thieno[3,2-d]pyrimidine-7-carboxamide;hydrochloride	1678649: Competitive inhibition of IRE1alpha LKR domain (Q470 to L997 residues) (unknown origin) expressed in Sf9 insect cells using mini-XBP-1 stem-loop RNA as substrate and measured every 2 mins for 50 mins by FRET assay	ic50	0.0300	uM
N-[4-[[3-[2-[(4-aminocyclohexyl)amino]pyrimidin-4-yl]-2-pyridinyl]oxy]naphthalen-1-yl]-2-chlorobenzenesulfonamide	1177292: Inhibition of human IRE1alpha using 5’[6FAM]-GAGUCCGCAGCACUC-[BHQ1]3’ substrate by biochemical fluorescence quenching assay	ic50	0.0310	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Thapsigargin	decreases reaction, increases phosphorylation, increases expression, affects splicing	12
Tunicamycin	decreases reaction, increases expression, increases phosphorylation, decreases sulfation	8
sodium arsenite	increases abundance, increases expression, increases reaction, affects reaction, increases secretion (+2 more)	6
4-phenylbutyric acid	decreases reaction, increases expression, increases phosphorylation, decreases expression	6
Arsenic Trioxide	increases expression, increases phosphorylation	5
Cadmium Chloride	increases phosphorylation, affects binding, increases reaction, decreases reaction, increases expression (+1 more)	5
Formaldehyde	increases expression, increases phosphorylation	4
bisphenol A	affects expression, affects cotreatment, increases methylation, increases expression	3
STF 083010	increases expression, decreases activity, decreases reaction	3
Bortezomib	affects phosphorylation, affects reaction, increases expression, increases response to substance, decreases response to substance	3
Acetylcysteine	decreases reaction, increases expression, increases abundance, increases phosphorylation, affects binding (+2 more)	3
Glucose	decreases reaction, increases phosphorylation, affects cotreatment	3
Paraquat	increases phosphorylation, increases reaction, increases expression	3
Particulate Matter	increases abundance, increases expression, decreases reaction, increases phosphorylation	3
AKT activator SC79	decreases reaction, increases expression	2
KIRA6	decreases reaction, increases expression, decreases activity	2
titanium dioxide	affects expression, increases expression	2
perfluorooctanoic acid	increases expression	2
perhexiline maleate	decreases reaction, increases abundance, increases expression	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, increases phosphorylation, affects reaction, decreases expression, increases cleavage	2
Resveratrol	decreases reaction, increases expression	2
Acetaminophen	increases expression	2
Ursolic Acid	decreases reaction, increases expression, increases activity	2
Arsenic	increases abundance, increases expression, increases reaction	2
Cadmium	decreases reaction, increases abundance, increases phosphorylation, increases expression	2
Capsaicin	increases expression	2
Curcumin	decreases expression, increases expression	2
Dithiothreitol	decreases activity, increases reaction, increases expression, increases oxidation, affects cotreatment	2
Estradiol	increases expression	2
Hydrogen Peroxide	decreases activity, increases oxidation, decreases reaction, increases expression	2

ChEMBL screening assays

180 unique, capped per target: 180 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1169227	Binding	Inhibition of ERN1 at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1RJ	Abcam HeLa ERN1 KO	Cancer cell line	Female
CVCL_D1SD	Abcam U-87MG ERN1 KO	Cancer cell line	Male
CVCL_D7PN	Ubigene A-549 ERN1 KO	Cancer cell line	Male
CVCL_D9EK	Ubigene HEK293 ERN1 KO	Transformed cell line	Female
CVCL_E0CW	Ubigene HeLa ERN1 KO	Cancer cell line	Female
CVCL_SM43	HAP1 ERN1 (-) 1	Cancer cell line	Male
CVCL_XN52	HAP1 ERN1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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