ERN2

Summary

ERN2 (endoplasmic reticulum to nucleus signaling 2, HGNC:16942) is a protein-coding gene on chromosome 16p12.2, encoding Serine/threonine-protein kinase/endoribonuclease IRE2 (Q76MJ5). Induces translational repression through 28S ribosomal RNA cleavage in response to ER stress.

Enables several functions, including ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including apoptotic chromosome condensation; negative regulation of DNA-templated transcription; and rRNA catabolic process. Located in cytosol and endoplasmic reticulum.

Source: NCBI Gene 10595 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 74 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_033266

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16942
Approved symbol	ERN2
Name	endoplasmic reticulum to nucleus signaling 2
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	IRE1b
Ensembl gene	ENSG00000134398
Ensembl biotype	protein_coding
OMIM	604034
Entrez	10595

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000256797, ENST00000457008, ENST00000561478, ENST00000562458, ENST00000562562, ENST00000566565, ENST00000569903, ENST00000885424, ENST00000885425, ENST00000885426, ENST00000885427, ENST00000885428, ENST00000885429, ENST00000885430, ENST00000885431, ENST00000885432, ENST00000885433

RefSeq mRNA: 2 — MANE Select: NM_033266 NM_001308220, NM_033266

CCDS: CCDS32407, CCDS76845

Canonical transcript exons

ENST00000256797 — 22 exons

Exon	Start	End
ENSE00001107253	23690310	23691043
ENSE00001107271	23700539	23700704
ENSE00001107291	23700959	23701114
ENSE00001107306	23692184	23692331
ENSE00001107309	23694728	23694927
ENSE00001107314	23695019	23695118
ENSE00001316879	23710172	23710244
ENSE00002610850	23713095	23713222
ENSE00003472520	23695200	23695389
ENSE00003562165	23702152	23702273
ENSE00003588358	23706754	23706861
ENSE00003615710	23695894	23695978
ENSE00003622668	23702390	23702537
ENSE00003627299	23710516	23710549
ENSE00003654782	23710913	23711018
ENSE00003677599	23702624	23702702
ENSE00003683610	23706330	23706431
ENSE00003684731	23704883	23705147
ENSE00003688466	23707007	23707079
ENSE00003756163	23691129	23691196
ENSE00003758369	23691963	23692090
ENSE00003760193	23691302	23691425

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 98.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5655 / max 98.7458, expressed in 57 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156781	0.5655	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	98.45	gold quality
pancreatic ductal cell	CL:0002079	97.20	gold quality
mucosa of transverse colon	UBERON:0004991	97.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.88	gold quality
olfactory bulb	UBERON:0002264	96.00	silver quality
epithelium of bronchus	UBERON:0002031	95.89	gold quality
bronchus	UBERON:0002185	95.72	gold quality
bronchial epithelial cell	CL:0002328	95.67	gold quality
colonic mucosa	UBERON:0000317	95.26	gold quality
rectum	UBERON:0001052	95.24	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.89	gold quality
type B pancreatic cell	CL:0000169	94.72	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	94.53	gold quality
triceps brachii	UBERON:0001509	94.39	silver quality
gluteal muscle	UBERON:0002000	93.87	silver quality
diaphragm	UBERON:0001103	93.63	silver quality
gall bladder	UBERON:0002110	93.53	gold quality
pylorus	UBERON:0001166	93.42	gold quality
buccal mucosa cell	CL:0002336	93.05	gold quality
cardia of stomach	UBERON:0001162	91.46	gold quality
trachea	UBERON:0003126	91.20	gold quality
cervix squamous epithelium	UBERON:0006922	90.99	silver quality
epithelial cell of pancreas	CL:0000083	89.75	silver quality
nasal cavity mucosa	UBERON:0001826	89.73	gold quality
vena cava	UBERON:0004087	89.42	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	89.08	silver quality
epithelium of nasopharynx	UBERON:0001951	88.42	gold quality
vastus lateralis	UBERON:0001379	88.29	silver quality
transverse colon	UBERON:0001157	87.96	gold quality
lateral globus pallidus	UBERON:0002476	87.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	49.51
E-ANND-3	yes	6.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting ERN2, 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-4713-3P	100.00	65.92	505
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-212-5P	96.83	67.43	950

Literature-anchored findings (GeneRIF, showing 8)

• The structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and unfolded protein response (UPR) signaling. (PMID:16973740)
• RNase domain of IRE1 determines the functional specificities of each of these isoforms. (PMID:18242182)
• Data show that IRE1beta represses translation on the ER membrane but not in the cytosol, and that this selective repression depends on the RNase activity of IRE1beta. (PMID:21146530)
• The luminal event mediated by IRE1beta involves direct interaction with unfolded proteins rather than association/dissociation with BiP. (PMID:23236464)
• ER stress-regulated IRE1 dependent decay is involved in regulation of hepatic diseases. (review) (PMID:27774654)
• A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in idiopathic pulmonary fibrosis (IPF), providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. (PMID:30973754)
• IRE1beta acts as a dominant-negative suppressor of IRE1alpha and affect how barrier epithelial cells manage the response to stress at the host-environment interface. (PMID:31985747)
• EEF1A2 and ERN2 could potentially discriminate metastatic status of mediastinal lymph node in lung adenocarcinomas harboring EGFR 19Del/L858R mutations. (PMID:32881299)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ern1	ENSDARG00000013997
danio_rerio		ENSDARG00000087767
mus_musculus	Ern2	ENSMUSG00000030866
rattus_norvegicus	Ern2	ENSRNOG00000018974
drosophila_melanogaster	Ire1	FBGN0261984
caenorhabditis_elegans		WBGENE00002147

Paralogs (1): ERN1 (ENSG00000178607)

Protein

Protein identifiers

Serine/threonine-protein kinase/endoribonuclease IRE2 — Q76MJ5 (reviewed: Q76MJ5)

Alternative names: Endoplasmic reticulum-to-nucleus signaling 2, Inositol-requiring protein 2, Ire1-beta

All UniProt accessions (5): E7ETG2, Q76MJ5, H3BSU1, H3BTW8, H3BUU2

UniProt curated annotations — full annotation on UniProt →

Function. Induces translational repression through 28S ribosomal RNA cleavage in response to ER stress. Pro-apoptotic. Appears to play no role in the unfolded-protein response, unlike closely related proteins.

Subcellular location. Endoplasmic reticulum membrane.

Post-translational modifications. Autophosphorylated.

Activity regulation. The kinase domain is activated by trans-autophosphorylation. Kinase activity is required for activation of the endoribonuclease domain.

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

RefSeq proteins (2): NP_001295149, NP_150296* (*=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 (51 total): sequence conflict 28, sequence variant 10, binding site 2, topological domain 2, domain 2, signal peptide 1, chain 1, mutagenesis site 1, transmembrane region 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9I3F	X-RAY DIFFRACTION	1.9
9I3U	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q76MJ5-F1	70.91	0.33

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): 637 (proton acceptor)

Ligand- & substrate-binding residues (2): 526–534; 548

Mutagenesis-validated functional residues (1):

Position	Phenotype
548	loss of autophosphorylation, of induction of apoptosis and of 28s rrna cleavage, attenuation of repression of protein sy

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 103 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOMF_NUCLEASE_ACTIVITY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CHROMOSOME_CONDENSATION, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_JNK_CASCADE, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (13): mRNA processing (GO:0006397), protein phosphorylation (GO:0006468), rRNA catabolic process (GO:0016075), apoptotic chromosome condensation (GO:0030263), response to endoplasmic reticulum stress (GO:0034976), IRE1-mediated unfolded protein response (GO:0036498), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of JNK cascade (GO:0046330), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), regulation of DNA-templated transcription (GO:0006355), RNA catabolic process (GO:0006401), apoptotic process (GO:0006915), endoplasmic reticulum unfolded protein response (GO:0030968)

GO Molecular Function (16): magnesium ion binding (GO:0000287), endonuclease activity (GO:0004519), RNA endonuclease activity (GO:0004521), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), hydrolase activity (GO:0016787), obsolete unfolded protein binding (GO:0051082), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), 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 (6): endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), endoplasmic reticulum quality control compartment (GO:0044322), IRE1-TRAF2-ASK1 complex (GO:1990604), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA-templated transcription	2
response to endoplasmic reticulum stress	2
nuclease activity	2
protein kinase activity	2
catalytic activity	2
cytoplasm	2
RNA processing	1
mRNA metabolic process	1
phosphorylation	1
protein modification process	1
RNA catabolic process	1
rRNA metabolic process	1
chromosome condensation	1
apoptotic nuclear changes	1
cellular response to stress	1
endoplasmic reticulum unfolded protein response	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
intrinsic apoptotic signaling pathway	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to unfolded protein	1
intracellular signal transduction	1
metal ion binding	1
endonuclease activity	1
RNA nuclease activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1

Protein interactions and networks

STRING

1268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERN2	XBP1	P17861	860
ERN2	ATF6	P18850	832
ERN2	ATF6B	Q99941	745
ERN2	HSPA5	P11021	726
ERN2	MBTPS2	O43462	571
ERN2	MBTPS1	Q14703	564
ERN2	EDEM1	Q92611	554
ERN2	DNAJC3	Q13217	547
ERN2	CREB3L3	Q68CJ9	526
ERN2	RTCB	Q9Y3I0	526
ERN2	ATF4	P18848	512
ERN2	DDIT3	P35638	511
ERN2	CANX	P27824	489
ERN2	DNAJB9	Q9UBS3	481
ERN2	ERO1A	Q96HE7	473

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ERN2	SEC16A	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): ERN2 (Co-fractionation), ERN2 (Synthetic Lethality), ERN2 (Affinity Capture-MS), SEC16A (Affinity Capture-MS), SEP15 (Affinity Capture-MS), UBR5 (Affinity Capture-MS), P4HB (Affinity Capture-MS), CNP (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), PDIA4 (Affinity Capture-MS), HSP90B1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), DNAJC3 (Affinity Capture-MS), KEAP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A3LUB9, B0XPE4, C0LGF4, C0LGL9, D2HHP1, G0RBE3, O64784, O65530, O94537, P32361, P39073, P45983, P45984, P49185, P49186, P49187, P49336, P53779, P79996, P92208, Q09499, Q17IE8, Q1EBK0, Q1XHL7, Q336M2, Q38SD2, Q3UHC2, Q4P9T2, Q4WJJ0, Q4WKP8, Q54IE8, Q557G1, Q559A2, Q55DJ8, Q55GJ2, Q61831, Q66KH9, Q6CCB0, Q6P3N6, Q751F5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3799 predictions. Top by Δscore:

Variant	Effect	Δscore
16:23691039:TGCTT:T	acceptor_gain	1.0000
16:23691041:CTT:C	acceptor_gain	1.0000
16:23691042:TT:T	acceptor_gain	1.0000
16:23691043:TCTG:T	acceptor_loss	1.0000
16:23691044:C:CC	acceptor_gain	1.0000
16:23691050:G:GC	acceptor_gain	1.0000
16:23691125:ATACC:A	donor_loss	1.0000
16:23691126:TACCT:T	donor_loss	1.0000
16:23691127:A:AC	donor_gain	1.0000
16:23691127:A:T	donor_loss	1.0000
16:23691128:C:CC	donor_gain	1.0000
16:23691128:C:CG	donor_loss	1.0000
16:23691192:CAGAT:C	acceptor_gain	1.0000
16:23691193:AGAT:A	acceptor_gain	1.0000
16:23691194:GAT:G	acceptor_gain	1.0000
16:23691195:ATC:A	acceptor_loss	1.0000
16:23691197:C:CC	acceptor_gain	1.0000
16:23692091:C:CC	acceptor_gain	1.0000
16:23692098:A:C	acceptor_gain	1.0000
16:23692195:T:TA	donor_gain	1.0000
16:23692332:C:CC	acceptor_gain	1.0000
16:23692339:C:CT	acceptor_gain	1.0000
16:23694726:A:AC	donor_gain	1.0000
16:23694727:C:CC	donor_gain	1.0000
16:23694727:CAGG:C	donor_gain	1.0000
16:23694727:CAGGA:C	donor_gain	1.0000
16:23694923:GTGCA:G	acceptor_gain	1.0000
16:23694924:TGCA:T	acceptor_gain	1.0000
16:23694925:GCA:G	acceptor_gain	1.0000
16:23694926:CA:C	acceptor_gain	1.0000

AlphaMissense

5943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:23695360:A:T	V547D	0.998
16:23695356:C:A	K548N	0.997
16:23695356:C:G	K548N	0.997
16:23691129:C:A	K856N	0.996
16:23691129:C:G	K856N	0.996
16:23695231:G:T	A590D	0.995
16:23694849:T:A	D660V	0.994
16:23691136:C:A	R854M	0.993
16:23691417:A:C	S795R	0.993
16:23691417:A:T	S795R	0.993
16:23691419:T:G	S795R	0.993
16:23694848:G:C	D660E	0.993
16:23694848:G:T	D660E	0.993
16:23690954:G:C	F886L	0.992
16:23690954:G:T	F886L	0.992
16:23690956:A:G	F886L	0.992
16:23691333:C:A	W823C	0.992
16:23691333:C:G	W823C	0.992
16:23691335:A:G	W823R	0.992
16:23691335:A:T	W823R	0.992
16:23694921:C:G	R636P	0.992
16:23695363:G:T	A546D	0.992
16:23695900:A:T	V535D	0.992
16:23691183:G:C	F838L	0.991
16:23691183:G:T	F838L	0.991
16:23691185:A:G	F838L	0.991
16:23710928:A:G	W62R	0.991
16:23710928:A:T	W62R	0.991
16:23694849:T:G	D660A	0.990
16:23695242:G:C	F586L	0.990

dbSNP variants (sampled 300 via entrez): RS1000585683 (16:23692848 T>C), RS1000609481 (16:23699862 C>G,T), RS1000642087 (16:23699568 T>C), RS1000860955 (16:23698155 T>C), RS1000904301 (16:23704031 G>A), RS1000956288 (16:23693148 G>A), RS1000968851 (16:23711727 T>C), RS1001001535 (16:23711409 T>C), RS1001072793 (16:23698425 C>G), RS1001141918 (16:23692674 T>A), RS1001286745 (16:23708013 G>A), RS1001309929 (16:23696065 T>G), RS1001356650 (16:23703829 C>T), RS1001403328 (16:23702335 G>A), RS1001454306 (16:23702097 TCCC>T,TCC,TCCCC)

Disease associations

OMIM: gene MIM:604034 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105932 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 14,126 (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
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL603469	LESTAURTINIB	3
CHEMBL3039525	GOLVATINIB	2	535
CHEMBL3408248	AZD-8186	1	1,161

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — IRE family

Binding affinities (BindingDB)

10 measured of 10 human assays (10 total across all organisms); most potent 10 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
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
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-[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-chloro-N-[2-fluoro-4-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]phenyl]benzenesulfonamide	IC50	117 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
N-(2-chlorophenyl)-4-methyl-3-[[5-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]-1,3-thiazol-4-yl]oxy]benzamide	IC50	228 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-chloro-N-[4-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxynaphthalen-1-yl]benzenesulfonamide	IC50	296 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
4-[4-[4-(1H-benzimidazol-2-ylmethyl)phenoxy]-1,3-thiazol-5-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine	IC50	439 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
1-(2-chlorophenyl)-N-[2-fluoro-4-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxyphenyl]methanesulfonamide	IC50	961 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
2-chloro-N-[2-fluoro-4-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyrazin-2-yl]oxyphenyl]benzenesulfonamide	IC50	6200 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors
4-[3-[4-(1H-benzimidazol-2-ylmethyl)phenoxy]pyrazin-2-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine	IC50	7300 nM	US-12391669: Substituted pyrimidines as IRE1 kinase inhibitors

ChEMBL bioactivities

12 potent at pChembl≥5 of 12 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.76	IC50	17.4	nM	STAUROSPORINE
7.66	IC50	22.1	nM	STAUROSPORINE
7.18	IC50	65.8	nM	STAUROSPORINE
6.94	Kd	116	nM	DABRAFENIB
6.54	Kd	292	nM	LESTAURTINIB
6.04	Kd	908	nM	K-252A
6.01	Kd	986	nM	GOLVATINIB
5.87	Kd	1337	nM	CHEMBL5653589
5.82	Kd	1500	nM	AZD-8186
5.77	ED50	1707	nM	CHEMBL5653589
5.67	Kd	2112	nM	CHEMBL3752910
5.57	ED50	2696	nM	CHEMBL3752910

PubChem BioAssay actives

10 with measured affinity, of 262 total; 8 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
(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	1715351: Inhibition of human ERN2 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0174	uM
Dabrafenib	1424998: 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	0.1160	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	1424998: 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	0.2920	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	1424998: 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	0.9080	uM
1-N’-[2-fluoro-4-[[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]-4-pyridinyl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1424998: 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	0.9860	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148337: Binding affinity to human ERN2 incubated for 45 mins by Kinobead based pull down assay	kd	1.3374	uM
8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide	1424998: 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	1.5000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148337: Binding affinity to human ERN2 incubated for 45 mins by Kinobead based pull down assay	kd	2.1119	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases abundance, affects expression, affects methylation, decreases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
aristolochic acid I	increases expression	1
beta-N-methylamino-L-alanine	decreases expression	1
chlortoluron	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
arsenic trichloride	decreases expression, increases abundance	1
CGP 52608	increases reaction, affects binding	1
Gold	increases expression	1
Quercetin	increases expression	1
T-2 Toxin	decreases expression, increases reaction, decreases reaction	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Cadmium Chloride	increases expression	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991711	Binding	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 ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

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