ORAI2

Summary

ORAI2 (ORAI calcium release-activated calcium modulator 2, HGNC:21667) is a protein-coding gene on chromosome 7q22.1, encoding Protein orai-2 (Q96SN7). Pore-forming subunit of inward rectifying Ca(2+) release-activated Ca(2+) (CRAC) channels.

Enables store-operated calcium channel activity. Involved in store-operated calcium entry. Located in plasma membrane.

Source: NCBI Gene 80228 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 57 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001126340

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21667
Approved symbol	ORAI2
Name	ORAI calcium release-activated calcium modulator 2
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CBCIP2, FLJ12474, FLJ14733, H_NH0514P08.8
Ensembl gene	ENSG00000160991
Ensembl biotype	protein_coding
OMIM	610929
Entrez	80228

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000356387, ENST00000403646, ENST00000473939, ENST00000478730, ENST00000482237, ENST00000488996, ENST00000495936, ENST00000498661, ENST00000611770, ENST00000952428

RefSeq mRNA: 4 — MANE Select: NM_001126340 NM_001126340, NM_001271818, NM_001271819, NM_032831

CCDS: CCDS5722

Canonical transcript exons

ENST00000495936 — 4 exons

Exon	Start	End
ENSE00001408887	102438944	102439181
ENSE00001409383	102436225	102436333
ENSE00001902201	102446513	102456825
ENSE00001930645	102433575	102433661

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1658 / max 252.8718, expressed in 1742 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80255	10.1658	1742

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	97.91	gold quality
ventral tegmental area	UBERON:0002691	97.18	gold quality
pylorus	UBERON:0001166	96.92	gold quality
superior vestibular nucleus	UBERON:0007227	96.53	gold quality
nipple	UBERON:0002030	96.30	gold quality
inferior vagus X ganglion	UBERON:0005363	96.09	gold quality
superior surface of tongue	UBERON:0007371	95.88	gold quality
trigeminal ganglion	UBERON:0001675	95.55	gold quality
pericardium	UBERON:0002407	95.18	gold quality
subthalamic nucleus	UBERON:0001906	95.09	gold quality
cardia of stomach	UBERON:0001162	94.94	gold quality
buccal mucosa cell	CL:0002336	94.55	gold quality
endothelial cell	CL:0000115	93.91	gold quality
lateral globus pallidus	UBERON:0002476	93.28	gold quality
stromal cell of endometrium	CL:0002255	93.09	gold quality
dorsal root ganglion	UBERON:0000044	92.99	gold quality
blood	UBERON:0000178	92.91	gold quality
substantia nigra pars compacta	UBERON:0001965	92.79	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.63	gold quality
saphenous vein	UBERON:0007318	92.59	gold quality
pons	UBERON:0000988	92.50	gold quality
pharyngeal mucosa	UBERON:0000355	92.49	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.31	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.19	gold quality
caecum	UBERON:0001153	90.91	gold quality
medulla oblongata	UBERON:0001896	90.83	gold quality
skin of hip	UBERON:0001554	90.69	gold quality
sperm	CL:0000019	89.98	gold quality
urethra	UBERON:0000057	89.74	gold quality
tongue	UBERON:0001723	89.57	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.73
E-MTAB-7381	no	180.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

326 targeting ORAI2, 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-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7162-3P	99.89	68.16	1682

Literature-anchored findings (GeneRIF, showing 18)

• Results suggest that Orai1, -2, and -3 channels are similarly inhibited by extracellular calcium, indicating similar affinities for Ca(2+) within the selectivity filter. (PMID:17452328)
• The effects of 2-aminoethoxydiphenyl borate on orai1, orai2, orai3 metabolism in HEK293 cells with and without STIM1 are reported. (PMID:18403424)
• analysis of activation of Orai1-3 channels by a STIM1 coiled-coil mutant (PMID:19506081)
• Data show that the fast Ca(2+)-dependent inactivation is mediated by three conserved glutamates in the C termini (CT) of Orai2 and Orai3, which show prominent fast Ca(2+)-dependent inactivation compared with Orai1. (PMID:19706554)
• With these data we show a new Ca(2)(+) entry pathway linked to the Ca(2)(+)/inositolphosphate second-messenger system in RPE cells which help to further understand regulatory pathways of agonists. (PMID:20607548)
• Orai1 and Orai2 operate in a STIM-dependent manner, Orai3 does not interact with STIM isoforms upon calcium store depletion in platelets. (PMID:22640869)
• Orai1 but not Orai2 plays a major role in the influx of extracellular Ca2+ into and mediator release from HLMCs following their activation (PMID:24040356)
• The higher amplitude of store-operated Ca2+ entry was associated to the over-expression for Stim2, Orai2-3, and TRPC1 while Stim2 levels remained constant and Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in primary myelofibrosis. (PMID:24603752)
• Orai1, Orai2 and STIM1 form functional Ca(2+) release-activated Ca(2+) channels in OUMS-27 cells (chondrocytes) and that these complexes are responsible for sustained Ca(2+) entry in response to agonist stimulation. (PMID:25769459)
• results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses. (PMID:26956485)
• findings provide evidence for a role for Orai1 and Orai2, in SOCE and migration in the human HL60 promyeloblastic cell line (PMID:27865925)
• ORAI1-3, are preferentially expressed in proximal tubular epithelial cells and downregulated in patients with diabetic nephropathy. (PMID:29203863)
• Higher expression of Orai2 was independently associated with a worse prognosis of patients with the classical and mesenchymal subtypes of glioblastoma.A strong association between Orai2 expression and apoptosis, stemness, and an epithelial-mesenchymal transition in the glioblastoma. (PMID:31772693)
• ORAI2 Down-Regulation Potentiates SOCE and Decreases Abeta42 Accumulation in Human Neuroglioma Cells. (PMID:32722509)
• Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-kappaB signalling. (PMID:32882268)
• Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. (PMID:32896813)
• ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly. (PMID:33310726)
• Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue. (PMID:34857756)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	orai2	ENSDARG00000035148
mus_musculus	Orai2	ENSMUSG00000039747
rattus_norvegicus	Orai2	ENSRNOG00000001427
drosophila_melanogaster	Orai	FBGN0041585
caenorhabditis_elegans		WBGENE00015648

Paralogs (2): ORAI3 (ENSG00000175938), ORAI1 (ENSG00000276045)

Protein

Protein identifiers

Protein orai-2 — Q96SN7 (reviewed: Q96SN7)

Alternative names: CAP-binding protein complex-interacting protein 2, Transmembrane protein 142B

All UniProt accessions (4): Q96SN7, C9J5L2, C9JQR7, C9JUY6

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of inward rectifying Ca(2+) release-activated Ca(2+) (CRAC) channels. Assembles with ORAI1 and ORAI3 to form hexameric CRAC channels that mediate Ca(2+) influx upon depletion of endoplasmic reticulum Ca(2+) store and channel activation by Ca(2+) sensor STIM1, a process known as store-operated Ca(2+) entry (SOCE). Various pore subunit combinations may account for distinct CRAC channel spatiotemporal and cell-type specific dynamics. ORAI1 mainly contributes to the generation of Ca(2+) plateaus involved in sustained Ca(2+) entry and is dispensable for cytosolic Ca(2+) oscillations, whereas ORAI2 and ORAI3 generate oscillatory patterns. CRAC channels assemble in Ca(2+) signaling microdomains where Ca(2+) influx is coupled to calmodulin and calcineurin signaling and activation of NFAT transcription factors recruited to ORAI1 via AKAP5. CRAC channels are the main pathway for Ca(2+) influx in T cells and promote the immune response to pathogens by activating NFAT-dependent cytokine and chemokine transcription.

Subunit / interactions. Oligomerizes in homomeric and heteromeric ORAI complexes. Native CRAC channels most likely consist of hexameric ORAI heteromers, implying that diverse ORAI1, ORAI2 and ORAI3 subunit combinations with distinct biophysical properties can operate in a cell-type specific way. Interacts with STIM1; this regulates channel activity. Interacts with CRACR2A/EFCAB4B.

Subcellular location. Cell membrane.

Activity regulation. CRAC channels are regulated by fast Ca(2+)-dependent inactivation (FCDI), a mechanism that limits Ca(2+) influx and cell toxicity. ORAI2 channels display prominent FCDI. Inhibited by lanthanides such as Gd(3+) ions.

Similarity. Belongs to the Orai family.

RefSeq proteins (4): NP_001119812, NP_001258747, NP_001258748, NP_116220 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012446	CRAC_channel	Family
IPR038350	Orai_sf	Homologous_superfamily

Pfam: PF07856

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (11 total): transmembrane region 4, mutagenesis site 4, chain 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96SN7-F1	80.59	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): 80 (confers selective permeability to ca(2+) ions)

Mutagenesis-validated functional residues (4):

Position	Phenotype
236	reduces fast ca(2+)-dependent inactivation; when associated with a-233 and a-235.
80	has dominant negative effect. impairs store-operated ca(2+) influx. decreases regenerative ca(2+) oscillations.
233	reduces fast ca(2+)-dependent inactivation; when associated with a-235 and a-236.
235	reduces fast ca(2+)-dependent inactivation; when associated with a-233 and a-236.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-139853	Elevation of cytosolic Ca2+ levels
R-HSA-5578775	Ion homeostasis
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers

MSigDB gene sets: 229 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_MONOATOMIC_CATION_TRANSPORT, FOSTER_TOLERANT_MACROPHAGE_DN, USF_01, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, LIAO_METASTASIS, RYTTCCTG_ETS2_B, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, SCHLOSSER_SERUM_RESPONSE_UP, SENESE_HDAC3_TARGETS_DN, TGGAAA_NFAT_Q4_01, MARSON_BOUND_BY_FOXP3_STIMULATED, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOMF_METAL_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY

GO Biological Process (5): store-operated calcium entry (GO:0002115), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (3): store-operated calcium channel activity (GO:0015279), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Platelet calcium homeostasis	1
Cardiac conduction	1
Signaling by the B Cell Receptor (BCR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion transport	2
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORAI2	STIM1	Q13586	999
ORAI2	STIM2	Q9P246	999
ORAI2	TRPC6	Q9Y210	983
ORAI2	ORAI3	Q9BRQ5	981
ORAI2	TRPC1	P48995	963
ORAI2	ORAI1	Q96D31	947
ORAI2	TRPC3	Q13507	872
ORAI2	TRPC4	Q9UBN4	825
ORAI2	TRPC5	Q9UL62	782
ORAI2	TRPM2	O94759	663
ORAI2	CACNA1C	Q13936	649
ORAI2	ITPR3	Q14573	645
ORAI2	ITPR1	Q14643	644
ORAI2	FKBP1A	P20071	564
ORAI2	SARAF	Q96BY9	552

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TRPC3	ORAI2	psi-mi:“MI:0915”(physical association)	0.400
STIM1	ORAI2	psi-mi:“MI:0915”(physical association)	0.400
CRACR2A	ORAI2	psi-mi:“MI:0915”(physical association)	0.400
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
	ORAI2	psi-mi:“MI:0915”(physical association)	0.000
COPS6	ORAI2	psi-mi:“MI:0915”(physical association)	0.000
ORAI2	GDF9	psi-mi:“MI:0915”(physical association)	0.000
ORAI2	SETDB1	psi-mi:“MI:0915”(physical association)	0.000
ORAI2	UNC119	psi-mi:“MI:0915”(physical association)	0.000
ORAI2	MED31	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): ORAI2 (Affinity Capture-RNA), MED31 (Two-hybrid), COPS6 (Two-hybrid), GDF9 (Two-hybrid), SETDB1 (Two-hybrid), UNC119 (Two-hybrid), ORAI2 (Affinity Capture-MS)

ESM2 similar proteins: A4FUY9, A5PN43, A7MBC7, D3ZWZ9, F4JTN2, O14524, P51811, Q0VGV9, Q32PG7, Q3SYY9, Q3ZBX1, Q49LS5, Q4V8X0, Q5EAU0, Q5F3F5, Q5GH61, Q5PQQ4, Q5PR61, Q5RDB4, Q5ZI05, Q5ZKY0, Q5ZLW2, Q68DH5, Q6AXF6, Q6AY05, Q6AZ61, Q6DFQ7, Q6NZI6, Q6P4P2, Q6Q3F5, Q7SYC7, Q7SYR6, Q7ZYA0, Q80UF9, Q8BH10, Q8BUV8, Q8C561, Q8K0B2, Q8R000, Q8TCT6

Diamond homologs: Q09232, Q5EAU0, Q5M848, Q5ZL05, Q5ZLW2, Q616J1, Q6AXR8, Q6NZI6, Q6P8G8, Q6TLE6, Q8BH10, Q8BWG9, Q96D31, Q96SN7, Q9BRQ5, Q9U6B8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	35
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1527380	GRCh37/hg19 7q22.1-31.31(chr7:100676872-119156160)	Pathogenic

SpliceAI

1023 predictions. Top by Δscore:

Variant	Effect	Δscore
7:102438942:A:AG	acceptor_gain	1.0000
7:102438942:AGCCT:A	acceptor_gain	1.0000
7:102438943:G:GG	acceptor_gain	1.0000
7:102438943:GCCT:G	acceptor_gain	1.0000
7:102438943:GCCTG:G	acceptor_gain	1.0000
7:102433659:CCGG:C	donor_loss	0.9900
7:102433660:CGG:C	donor_loss	0.9900
7:102433661:GGTG:G	donor_loss	0.9900
7:102433662:G:GG	donor_gain	0.9900
7:102433662:GTGA:G	donor_loss	0.9900
7:102433663:T:A	donor_loss	0.9900
7:102438938:CCTTA:C	acceptor_loss	0.9900
7:102438939:CTTA:C	acceptor_loss	0.9900
7:102438940:TTA:T	acceptor_loss	0.9900
7:102438941:TA:T	acceptor_loss	0.9900
7:102438942:A:C	acceptor_loss	0.9900
7:102438943:G:A	acceptor_loss	0.9900
7:102438943:GC:G	acceptor_gain	0.9900
7:102438943:GCC:G	acceptor_gain	0.9900
7:102439178:CATGG:C	donor_loss	0.9900
7:102439179:ATGGT:A	donor_loss	0.9900
7:102439182:G:A	donor_loss	0.9900
7:102439182:G:GG	donor_gain	0.9900
7:102439183:T:TC	donor_loss	0.9900
7:102439184:G:GG	donor_loss	0.9900
7:102441786:C:G	donor_gain	0.9900
7:102446509:GCA:G	acceptor_loss	0.9900
7:102446510:CAGG:C	acceptor_loss	0.9900
7:102446511:A:AG	acceptor_gain	0.9900
7:102446511:AGGT:A	acceptor_gain	0.9900

AlphaMissense

1476 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:102439114:T:C	L53P	1.000
7:102439120:T:C	L55P	1.000
7:102439126:G:T	R57M	1.000
7:102439133:G:C	K59N	1.000
7:102439133:G:T	K59N	1.000
7:102439135:T:A	L60Q	1.000
7:102439135:T:C	L60P	1.000
7:102439139:G:C	K61N	1.000
7:102439139:G:T	K61N	1.000
7:102439156:C:A	S67Y	1.000
7:102439156:C:T	S67F	1.000
7:102439162:T:A	L69H	1.000
7:102439162:T:C	L69P	1.000
7:102439165:T:A	L70H	1.000
7:102439170:G:C	G72R	1.000
7:102439171:G:A	G72D	1.000
7:102439173:T:C	F73L	1.000
7:102439174:T:C	F73S	1.000
7:102439174:T:G	F73C	1.000
7:102439175:T:A	F73L	1.000
7:102439175:T:G	F73L	1.000
7:102439177:C:A	A74D	1.000
7:102439180:T:A	M75K	1.000
7:102446613:T:C	L109P	1.000
7:102446622:T:C	L112P	1.000
7:102446630:A:C	S115R	1.000
7:102446632:C:A	S115R	1.000
7:102446632:C:G	S115R	1.000
7:102446643:T:C	L119P	1.000
7:102446735:T:A	W150R	1.000

dbSNP variants (sampled 300 via entrez): RS1000151807 (7:102443380 G>A), RS1000233651 (7:102454668 C>G), RS1000248964 (7:102431995 G>T), RS1000357573 (7:102438399 T>G), RS1000447728 (7:102433208 C>G,T), RS1000796038 (7:102442731 C>T), RS1000827714 (7:102436913 G>A,T), RS1000828595 (7:102443389 C>T), RS1000835520 (7:102455848 C>G), RS1000893368 (7:102438220 C>T), RS1001015821 (7:102447849 G>A,T), RS1001094471 (7:102437102 T>C), RS1001115298 (7:102453231 C>T), RS1001192508 (7:102434177 C>G,T), RS1001251205 (7:102433873 C>A)

Disease associations

OMIM: gene MIM:610929 | 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
GCST003837_4	Chronotype	8.000000e-15
GCST003838_4	Morning vs. evening chronotype	7.000000e-07
GCST007576_427	Chronotype	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3038476 (PROTEIN FAMILY), CHEMBL4888450 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 257 (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
CHEMBL4753998	ZEGOCRACTIN	2	257

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Orai channels

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
zegocractin	Inhibition	6.05	pIC50
GSK-7975A	Inhibition	5.84	pIC50

ChEMBL bioactivities

36 potent at pChembl≥5 of 65 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.05	IC50	895	nM	ZEGOCRACTIN
5.80	IC50	1600	nM	CHEMBL2386009
5.68	IC50	2100	nM	CHEMBL2386172
5.66	IC50	2200	nM	CHEMBL2386000
5.62	IC50	2400	nM	CHEMBL2386180
5.57	IC50	2700	nM	CHEMBL2386179
5.55	IC50	2800	nM	CHEMBL2386186
5.50	IC50	3200	nM	CHEMBL2386172
5.47	IC50	3400	nM	CHEMBL2386185
5.46	IC50	3500	nM	CHEMBL2386180
5.31	IC50	4900	nM	CHEMBL2386185
5.29	IC50	5100	nM	CHEMBL2385996
5.23	IC50	5900	nM	CHEMBL2386174
5.22	IC50	6000	nM	CHEMBL2386000
5.19	IC50	6400	nM	CHEMBL2386184
5.16	IC50	6900	nM	CHEMBL2386005
5.14	IC50	7200	nM	CHEMBL2386186
5.13	IC50	7400	nM	CHEMBL2386009
5.12	IC50	7600	nM	CHEMBL2386171
5.11	IC50	7700	nM	CHEMBL2386181
5.10	IC50	7900	nM	CHEMBL2385999
5.10	IC50	8000	nM	CHEMBL2385998
5.09	IC50	8200	nM	CHEMBL2385999
5.07	IC50	8600	nM	CHEMBL2386179
5.06	IC50	8700	nM	DIPHENYL BORINIC ACID
5.05	IC50	9000	nM	CHEMBL2386174
5.05	IC50	8900	nM	CHEMBL2385997
5.05	IC50	8900	nM	CHEMBL2385996
5.03	IC50	9300	nM	CHEMBL2386177
5.02	IC50	9500	nM	CHEMBL2386171
5.01	IC50	9800	nM	CHEMBL2386177
5.01	IC50	9800	nM	CHEMBL2386004
5.01	IC50	9800	nM	DIPHENYL BORINIC ACID
5.00	IC50	9900	nM	CHEMBL2386178
5.00	IC50	1.01e+04	nM	CHEMBL2385998
5.00	IC50	1e+04	nM	CHEMBL2386178

PubChem BioAssay actives

35 with measured affinity, of 83 total; 21 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
N-[5-(6-chloro-2,2-difluoro-1,3-benzodioxol-5-yl)pyrazin-2-yl]-2-fluoro-6-methylbenzamide	1774821: Inhibition of Orai2/STIM1 (unknown origin)	ic50	0.8950	uM
2,2-bis(4-methylphenyl)-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	1.6000	uM
2,2-bis[4-(trifluoromethyl)phenyl]-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.1000	uM
1,1-diphenyl-2-oxa-8-aza-5-azonia-1-boranuidaspiro[4.5]decane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.2000	uM
2-(4-butylphenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.4000	uM
2-(4-methylphenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.7000	uM
2-(4-iodophenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.8000	uM
2-(4-bromophenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	3.4000	uM
3,3-dimethyl-2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	5.1000	uM
2,2-bis(4-fluorophenyl)-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	5.9000	uM
(4-chlorophenyl)-phenylborinic acid	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	6.4000	uM
(4S)-4-(1H-indol-3-ylmethyl)-2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclopentan-5-one	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	6.9000	uM
bis[4-(trifluoromethyl)phenyl]borinic acid	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	7.6000	uM
2-phenyl-2-(4-phenylphenyl)-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	7.7000	uM
2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclohexane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	7.9000	uM
(5R)-2,2-diphenyl-3-oxa-1-azonia-2-boranuidabicyclo[3.3.0]octane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	8.0000	uM
diphenylborinic acid	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	8.7000	uM
(5S)-2,2-diphenyl-3-oxa-1-azonia-2-boranuidabicyclo[3.3.0]octane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	8.9000	uM
2-(4-fluorophenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	9.3000	uM
(4S)-4-(hydroxymethyl)-2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclopentan-5-one	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	9.8000	uM
2-(2-methylphenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Air Pollutants	increases expression, affects expression, increases abundance	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases abundance, affects cotreatment, decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Bortezomib	decreases expression	1
Sunitinib	decreases expression	1
Benzene	increases expression	1
Doxorubicin	decreases expression	1
Lead	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Oils	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2388390	Binding	Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport. — Bioorg Med Chem

Clinical trials (associated diseases)

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