SLC9A2

Summary

SLC9A2 (solute carrier family 9 member A2, HGNC:11072) is a protein-coding gene on chromosome 2q12.1, encoding Sodium/hydrogen exchanger 2 (Q9UBY0). Plasma membrane Na(+)/H(+) antiporter.

This gene encodes a member of the sodium-hydrogen exchanger (NHE) protein family. These proteins are involved in sodium-ion transport by exchanging intracellular hydrogen ions to external sodium ions and help in the regulation of cell pH and volume. The encoded protein is localized to the apical membrane and is involved in apical absorption of sodium.

Source: NCBI Gene 6549 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 83 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003048

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11072
Approved symbol	SLC9A2
Name	solute carrier family 9 member A2
Location	2q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115616
Ensembl biotype	protein_coding
OMIM	600530
Entrez	6549

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000233969, ENST00000467657, ENST00000469286, ENST00000907277, ENST00000907278

RefSeq mRNA: 1 — MANE Select: NM_003048 NM_003048

CCDS: CCDS2062

Canonical transcript exons

ENST00000233969 — 12 exons

Exon	Start	End
ENSE00000772486	102657564	102658027
ENSE00000772487	102665100	102665350
ENSE00000772488	102683261	102683478
ENSE00000772489	102684134	102684336
ENSE00000772493	102702406	102702502
ENSE00000772494	102704544	102704675
ENSE00000772495	102705846	102705936
ENSE00000804374	102619553	102620137
ENSE00001305086	102708119	102711355
ENSE00003521352	102694414	102694503
ENSE00003550942	102695043	102695113
ENSE00003580332	102701070	102701231

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 90.81.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8543 / max 40.0530, expressed in 225 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21767	0.5367	151
21766	0.3136	159
21769	0.0040	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	90.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.28	gold quality
mucosa of transverse colon	UBERON:0004991	82.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	78.75	gold quality
buccal mucosa cell	CL:0002336	78.56	gold quality
colonic mucosa	UBERON:0000317	77.59	gold quality
transverse colon	UBERON:0001157	76.99	gold quality
pylorus	UBERON:0001166	76.01	gold quality
stomach	UBERON:0000945	75.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.12	gold quality
body of stomach	UBERON:0001161	75.06	gold quality
colonic epithelium	UBERON:0000397	73.39	gold quality
gastrocnemius	UBERON:0001388	72.55	gold quality
muscle of leg	UBERON:0001383	71.89	gold quality
duodenum	UBERON:0002114	69.29	gold quality
fundus of stomach	UBERON:0001160	67.77	gold quality
skeletal muscle organ	UBERON:0014892	67.36	gold quality
muscle organ	UBERON:0001630	67.35	gold quality
cardia of stomach	UBERON:0001162	66.90	gold quality
minor salivary gland	UBERON:0001830	65.43	gold quality
left testis	UBERON:0004533	65.21	gold quality
adult mammalian kidney	UBERON:0000082	65.10	gold quality
right testis	UBERON:0004534	64.94	gold quality
large intestine	UBERON:0000059	64.90	gold quality
colon	UBERON:0001155	64.86	gold quality
testis	UBERON:0000473	64.47	gold quality
intestine	UBERON:0000160	64.17	gold quality
vermiform appendix	UBERON:0001154	63.51	gold quality
saliva-secreting gland	UBERON:0001044	62.95	gold quality
mucosa of stomach	UBERON:0001199	62.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDX2, EGR1, EP300, MYOD1, NFKB1, NFKB, RELA, SP1, SP3, SP4, ZNF354C

miRNA regulators (miRDB)

164 targeting SLC9A2, 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-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797

Literature-anchored findings (GeneRIF, showing 14)

• In humans, NHE2 transcripts appear to be gestationally regulated, which may contribute to changes in NHE activity. (PMID:15664417)
• expression of the human NHE2 promoter is controlled by Sp1 and Sp3 by interactions with the proximal promoter and the transcription initiation site of NHE2 (PMID:17561809)
• No mutation was found in the coding regions and intron-exon boundaries of the genes for CA II, CA IV, CA XIV, kNCB1, NHE3, NHE8, NHRF1, NHRF2 and SLC26A6 amplified from genomic DNA of family members with pRTA. (PMID:17881426)
• T84 human colon cells contain three isoforms of the Na+/H+ exchanger, NHE1, NHE2, and NHE4, but not the Cl-dependent NHE (PMID:17943310)
• Functional coupling of the downregulated in adenoma Cl-/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3 in intestinal epithelial cells. (PMID:19056765)
• Report morphological adaptation with preserved proliferation/NHE2 content in the colon of patients with short bowel syndrome. (PMID:19389806)
• The functional and molecular expression of NHEs in cultured human endolymphatic sac (ES) epithelial cells was determined and the effect of IFN-gamma on NHE function, was examined. (PMID:19479940)
• Phosphorylation of nPKC-delta results in activation of ERK1/2 kinase and subsequent induction of Egr-1. Subsequently, Egr-1 directly targets NHE2 promoter and promotes NHE2 transcriptional upregulation by interaction with NHE2-PMA response element. (PMID:22052014)
• These data indicate that the acid-dependent NHE2 stimulation is implemented by transcriptional upregulation of NHE2 via acid-induced Egr-1 in the intestinal epithelial cells. (PMID:24376510)
• Studies show that phosphorylation of the NHE3 at a single amino acid in the distal part of the C-terminus affects multiple aspects of NHE3 complex formation and changes the NHE3 lipid raft distribution, which cause changes in specific aspects of basal as well as acutely stimulated and inhibited Na(+)/H(+) exchange activity. (PMID:28495796)
• Differentiated Caco-2BBe cells display particularly high mRNA expression levels of NHE2, which can be functionally identified in the apical membrane. Although at low intracellular pH, NHE2 transport rate was far lower than that of NHE1. NHE2 activity was nevertheless essential for the maintenance of the steady-state pHi of these cells. (PMID:30977986)
• Functional characterization of the sodium/hydrogen exchanger 8 and its role in proliferation of colonic epithelial cells. (PMID:34288721)
• zDHHC3-mediated S-palmitoylation of SLC9A2 regulates apoptosis in kidney clear cell carcinoma. (PMID:38619631)
• Identification and Validation of SLC9A2 as A Potential Tumor Suppressor in Colorectal Cancer: Integrating Bioinformatics Analysis with Experimental Confirmation. (PMID:38809379)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc9a2	ENSDARG00000058780
mus_musculus	Slc9a2	ENSMUSG00000026062
rattus_norvegicus	Slc9a2	ENSRNOG00000015567
drosophila_melanogaster	Nhe3	FBGN0028703
drosophila_melanogaster	Nhe2	FBGN0040297
caenorhabditis_elegans		WBGENE00003730
caenorhabditis_elegans		WBGENE00003732
caenorhabditis_elegans		WBGENE00003733
caenorhabditis_elegans		WBGENE00003734

Paralogs (10): SLC9A7 (ENSG00000065923), SLC9A3 (ENSG00000066230), SLC9A1 (ENSG00000090020), SLC9A5 (ENSG00000135740), SLC9C2 (ENSG00000162753), SLC9C1 (ENSG00000172139), SLC9A4 (ENSG00000180251), SLC9A9 (ENSG00000181804), SLC9A8 (ENSG00000197818), SLC9A6 (ENSG00000198689)

Protein

Protein identifiers

Sodium/hydrogen exchanger 2 — Q9UBY0 (reviewed: Q9UBY0)

Alternative names: Na(+)/H(+) exchanger 2, Solute carrier family 9 member 2

All UniProt accessions (1): Q9UBY0

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane Na(+)/H(+) antiporter. Mediates the electroneutral exchange of intracellular H(+) ions for extracellular Na(+). Major apical Na(+)/H(+) exchanger in the base of the colonic crypt. Controls in the colonic crypt intracellular pH (pHi) to direct colonic epithelial cell differentiation into the absorptive enterocyte lineage at the expense of the secretory lineage.

Subunit / interactions. Interacts with CHP1 and CHP2.

Subcellular location. Apical cell membrane.

Tissue specificity. Expressed in skeletal muscle, colon and kidney. Lower levels in the testis, prostate, ovary, and small intestine. In the distal colon, expressed along the cryptal axis.

Similarity. Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.

RefSeq proteins (1): NP_003039* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001953	NHE-2/4	Family
IPR004709	NaH_exchanger	Family
IPR006153	Cation/H_exchanger_TM	Domain
IPR018422	Cation/H_exchanger_CPA1	Family
IPR032103	NHE_CaM-bd	Domain

Pfam: PF00999, PF16644

Catalyzed reactions (Rhea), 1 shown:

• Na(+)(in) + H(+)(out) = Na(+)(out) + H(+)(in) (RHEA:29419)

UniProt features (21 total): transmembrane region 12, compositionally biased region 3, region of interest 2, sequence variant 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBY0-F1	66.40	0.16

Functional residue map

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

Glycosylation sites (1): 350

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-425986	Sodium/Proton exchangers
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 135 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, chr2q12, GOBP_MONOATOMIC_CATION_TRANSPORT, GTGCCTT_MIR506, GOBP_INTRACELLULAR_SODIUM_ION_HOMEOSTASIS, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, TGACATY_UNKNOWN, GOBP_SODIUM_ION_HOMEOSTASIS, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, TTGGAGA_MIR5155P_MIR519E, GOBP_REGULATION_OF_PH

GO Biological Process (11): monoatomic ion transport (GO:0006811), intracellular protein localization (GO:0008104), epithelial cell differentiation (GO:0030855), regulation of intracellular pH (GO:0051453), potassium ion transmembrane transport (GO:0071805), sodium ion import across plasma membrane (GO:0098719), monoatomic cation transport (GO:0006812), sodium ion transport (GO:0006814), regulation of pH (GO:0006885), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (3): sodium:proton antiporter activity (GO:0015385), potassium:proton antiporter activity (GO:0015386), antiporter activity (GO:0015297)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metal ion SLC transporters	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
monoatomic cation transmembrane transport	2
metal cation:proton antiporter activity	2
macromolecule localization	1
cell differentiation	1
epithelium development	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
potassium ion transport	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
monoatomic ion transport	1
metal ion transport	1
monoatomic cation homeostasis	1
biological regulation	1
cellular process	1
sodium ion transmembrane transporter activity	1
solute:potassium antiporter activity	1
secondary active transmembrane transporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1

Protein interactions and networks

STRING

980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC9A2	SLC9B2	Q86UD5	899
SLC9A2	SLC26A3	P40879	716
SLC9A2	SLC4A1	P02730	673
SLC9A2	SLC26A6	Q9BXS9	663
SLC9A2	SLC4A7	Q9Y6M7	661
SLC9A2	SLC4A4	Q9Y6R1	617
SLC9A2	NHERF1	O14745	616
SLC9A2	RHBG	Q9H310	602
SLC9A2	CHP1	Q99653	563
SLC9A2	SLC12A2	P55011	561
SLC9A2	SLC12A1	Q13621	554
SLC9A2	SLC9B1	Q4ZJI4	522
SLC9A2	SLC4A2	P04920	520
SLC9A2	ATP1A4	Q13733	520
SLC9A2	SLC4A8	Q2Y0W8	520

IntAct

5 interactions, top by confidence:

A	B	Type	Score
CFTR	LPAR2	psi-mi:“MI:0914”(association)	0.500
SLC9A2	SPTAN1	psi-mi:“MI:0915”(physical association)	0.400
SLC9A2	MEIOC	psi-mi:“MI:0914”(association)	0.350

BioGRID (130): SLC9A2 (Reconstituted Complex), SLC9A2 (Reconstituted Complex), SRC (Reconstituted Complex), RASA1 (Reconstituted Complex), SPTA1 (Reconstituted Complex), ABL1 (Reconstituted Complex), SLC9A2 (Proximity Label-MS), SLC9A2 (Affinity Capture-MS), SLC9A2 (Affinity Capture-MS), AKAP11 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), ANK3 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKRD27 (Affinity Capture-MS), APBA2 (Affinity Capture-MS)

ESM2 similar proteins: A1L3P4, A4IHB9, D3ZJ86, D4A7H1, F7B113, O00341, O16452, O54701, P19634, P23791, P26431, P26432, P26434, P31596, P35449, P43004, P43006, P48761, P48762, P48763, P48764, P50482, Q01345, Q28036, Q3ZAS0, Q4R335, Q56XP4, Q61165, Q68KI4, Q6AI14, Q6DFC0, Q84WG1, Q8BLV3, Q8BUE1, Q8BUN9, Q8BYR8, Q8BZ00, Q8IVB4, Q8JZR4, Q8RWU6

Diamond homologs: A1L3P4, B2RXE2, D3ZJ86, D4A7H1, F7B113, G3X939, G5EBK1, M5A7P9, O13726, O16452, P19634, P23791, P26431, P26432, P26433, P26434, P35449, P48761, P48762, P48763, P48764, P50482, Q01345, Q14940, Q28036, Q28362, Q3ZAS0, Q4L208, Q56XP4, Q61165, Q6AI14, Q84WG1, Q8BLV3, Q8BUE1, Q8BZ00, Q8IVB4, Q8R4D1, Q8RWU6, Q8S396, Q8T5S1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SLC9A2	“down-regulates quantity”	hydron	relocalization
SLC9A2	“up-regulates quantity”	sodium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2789 predictions. Top by Δscore:

Variant	Effect	Δscore
2:102620133:GATTG:G	donor_gain	1.0000
2:102620134:A:G	donor_gain	1.0000
2:102620134:ATTGG:A	donor_loss	1.0000
2:102620135:TTG:T	donor_gain	1.0000
2:102620135:TTGGT:T	donor_loss	1.0000
2:102620138:G:GG	donor_gain	1.0000
2:102620138:GTGAG:G	donor_loss	1.0000
2:102620139:T:A	donor_loss	1.0000
2:102665095:TGCA:T	acceptor_loss	1.0000
2:102665097:CAGGT:C	acceptor_loss	1.0000
2:102665098:A:AC	acceptor_loss	1.0000
2:102665098:A:AG	acceptor_gain	1.0000
2:102665099:G:GT	acceptor_gain	1.0000
2:102665099:GGTC:G	acceptor_gain	1.0000
2:102665346:ATGGC:A	donor_gain	1.0000
2:102665347:TGGC:T	donor_gain	1.0000
2:102665347:TGGCG:T	donor_loss	1.0000
2:102665348:GGC:G	donor_gain	1.0000
2:102665348:GGCG:G	donor_gain	1.0000
2:102665349:GC:G	donor_gain	1.0000
2:102665349:GCG:G	donor_gain	1.0000
2:102665349:GCGTA:G	donor_loss	1.0000
2:102665350:CG:C	donor_loss	1.0000
2:102665351:G:GG	donor_gain	1.0000
2:102665351:GTAA:G	donor_loss	1.0000
2:102665352:TA:T	donor_loss	1.0000
2:102665353:AA:A	donor_loss	1.0000
2:102683260:GA:G	acceptor_gain	1.0000
2:102683469:C:T	donor_gain	1.0000
2:102683478:GGTAA:G	donor_gain	1.0000

AlphaMissense

5321 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:102657714:C:A	P147Q	1.000
2:102657726:T:C	L151P	1.000
2:102665211:G:C	G289R	1.000
2:102665223:G:C	G293R	1.000
2:102665224:G:A	G293D	1.000
2:102665278:C:A	P311Q	1.000
2:102665298:A:C	S318R	1.000
2:102665300:T:A	S318R	1.000
2:102665300:T:G	S318R	1.000
2:102683306:T:A	N350K	1.000
2:102683306:T:G	N350K	1.000
2:102683320:C:T	S355F	1.000
2:102683379:T:C	F375L	1.000
2:102683381:C:A	F375L	1.000
2:102683381:C:G	F375L	1.000
2:102701173:G:C	A564P	1.000
2:102620107:T:A	W87R	0.999
2:102620107:T:C	W87R	0.999
2:102620120:C:A	A91D	0.999
2:102620129:C:A	A94D	0.999
2:102657564:G:A	G97D	0.999
2:102657566:T:C	F98L	0.999
2:102657568:C:A	F98L	0.999
2:102657568:C:G	F98L	0.999
2:102657605:A:C	S111R	0.999
2:102657607:C:A	S111R	0.999
2:102657607:C:G	S111R	0.999
2:102657608:T:C	C112R	0.999
2:102657615:T:C	L114P	0.999
2:102657626:G:A	G118R	0.999

dbSNP variants (sampled 300 via entrez): RS1000001860 (2:102693168 T>C), RS1000023439 (2:102711321 A>G), RS1000054840 (2:102629907 T>C,G), RS1000061282 (2:102699870 T>C), RS1000075273 (2:102669693 C>G), RS1000091887 (2:102699639 G>A), RS1000132502 (2:102677627 T>C), RS1000152266 (2:102642062 T>TAAC), RS1000198297 (2:102675390 T>A), RS1000205174 (2:102641898 G>A,C), RS1000452870 (2:102625226 T>A,C), RS1000473830 (2:102647149 T>G), RS1000480978 (2:102636519 C>A,T), RS1000508803 (2:102660988 G>A), RS1000509696 (2:102649988 A>G)

Disease associations

OMIM: gene MIM:600530 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): acute megakaryoblastic leukemia (MONDO:0018872), mediastinal germ cell tumor (MONDO:0021067)

Orphanet (1): Acute megakaryoblastic leukemia (Orphanet:518)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003542_105	Night sleep phenotypes	9.000000e-06
GCST003875_31	Gut microbiota (bacterial taxa)	8.000000e-11
GCST005851_3	Delirium	1.000000e-08
GCST007563_2	Allergic disease (asthma, hay fever or eczema)	4.000000e-24
GCST007564_34	Asthma or allergic disease (pleiotropy)	2.000000e-27
GCST008916_108	Asthma	1.000000e-22
GCST008916_29	Asthma	2.000000e-60
GCST90002400_322	Plateletcrit	7.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0007985	platelet crit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007947	Leukemia, Megakaryoblastic, Acute	C04.557.337.539.275.450; C15.378.508.539.275.450

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3133 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,048 (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
CHEMBL355862	ZONIPORIDE	2	241
CHEMBL436559	CARIPORIDE	2	1,678
CHEMBL64360	ENIPORIDE	2	129

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC9 family of sodium/hydrogen exchangers

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

Ligand	Action	Affinity	Parameter
amiloride	Inhibition	7.1	pKi

ChEMBL bioactivities

20 potent at pChembl≥5 of 31 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	IC50	70	nM	CHEMBL3900457
6.64	IC50	231	nM	BI 9627
6.51	IC50	310	nM	CHEMBL3957275
6.51	IC50	310	nM	CHEMBL3974005
6.37	IC50	430	nM	CHEMBL3980085
6.37	IC50	430	nM	CHEMBL3900790
5.75	IC50	1800	nM	CHEMBL51879
5.70	IC50	2000	nM	ENIPORIDE
5.41	IC50	3900	nM	CHEMBL352933
5.37	IC50	4300	nM	CARIPORIDE
5.05	IC50	9000	nM	CHEMBL217698
5.04	IC50	9200	nM	ENIPORIDE

PubChem BioAssay actives

4 with measured affinity, of 14 total; 4 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
trans-(1R,3R)-N-(diaminomethylidene)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropane-1-carboxamide	143807: Compound is screened in AP1 cells expressing human NHE-2 for sodium hydrogen exchange activity	ic50	1.8000	uM
N-(diaminomethylidene)-5-methyl-1-phenylpyrazole-4-carboxamide	143808: In vitro concentration of compound required to inhibit NHE-2 mediated intracellular maximal pH recovery by 50%	ic50	3.9000	uM
5-(4-fluoro-3-methylphenyl)-2-methoxy-4-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]pyrimidine	270791: Inhibition of human NHE2 expressed in Ap1 cell line	ic50	9.0000	uM
N-(diaminomethylidene)-2-methyl-5-methylsulfonyl-4-pyrrol-1-ylbenzamide	143808: In vitro concentration of compound required to inhibit NHE-2 mediated intracellular maximal pH recovery by 50%	ic50	9.2000	uM

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
ethyl-p-hydroxybenzoate	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Decitabine	affects cotreatment, increases expression	1
Cocaine	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Protons	affects transport	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	affects methylation	1
Cadmium Chloride	increases expression	1
Palmitic Acid	decreases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

10 unique, capped per target: 8 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3861048	Binding	Inhibition of human NHE2 expressed in LAP1 cell assessed as intracellular pH recovery measured for 2 mins by CECF-AM dye based FLIPR assay	Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na+/H+ Exchanger Type 3 (NHE3). — J Med Chem
CHEMBL748617	Functional	In vitro concentration of compound required to inhibit NHE-2 mediated intracellular maximal pH recovery by 50%	Discovery of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4WD	LS180-SLC9A2-KO-c2	Cancer cell line	Female
CVCL_D4WE	LS180-SLC9A2-KO-c8	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04083170	PHASE2	TERMINATED	Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers
NCT00392353	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
NCT01823198	PHASE1/PHASE2	COMPLETED	Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies
NCT02530619	Not specified	UNKNOWN	Alisertib in Treating Patients With Myelofibrosis or Relapsed or Refractory Acute Megakaryoblastic Leukemia