FOLR2

Summary

FOLR2 (folate receptor beta, HGNC:3793) is a protein-coding gene on chromosome 11q13.4, encoding Folate receptor beta (P14207). Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells.

The protein encoded by this gene is a member of the folate receptor (FOLR) family, and these genes exist in a cluster on chromosome 11. Members of this gene family have a high affinity for folic acid and for several reduced folic acid derivatives, and they mediate delivery of 5-methyltetrahydrofolate to the interior of cells. This protein has a 68% and 79% sequence homology with the FOLR1 and FOLR3 proteins, respectively. Although this protein was originally thought to be specific to placenta, it can also exist in other tissues, and it may play a role in the transport of methotrexate in synovial macrophages in rheumatoid arthritis patients. Multiple transcript variants that encode the same protein have been found for this gene.

Source: NCBI Gene 2350 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 41 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000803

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3793
Approved symbol	FOLR2
Name	folate receptor beta
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	FRβ
Ensembl gene	ENSG00000165457
Ensembl biotype	protein_coding
OMIM	136425
Entrez	2350

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000298223, ENST00000321324, ENST00000449475, ENST00000454954, ENST00000535625, ENST00000536778, ENST00000538353, ENST00000539412, ENST00000541003, ENST00000868542, ENST00000868543, ENST00000943224, ENST00000943225, ENST00000943226, ENST00000943227, ENST00000943228

RefSeq mRNA: 4 — MANE Select: NM_000803 NM_000803, NM_001113534, NM_001113535, NM_001113536

CCDS: CCDS8212

Canonical transcript exons

ENST00000298223 — 5 exons

Exon	Start	End
ENSE00002235666	72216794	72216925
ENSE00002314479	72221470	72221950
ENSE00002492402	72220870	72221058
ENSE00002533341	72221176	72221311
ENSE00003565580	72218561	72218734

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 97.07.

FANTOM5 (CAGE): breadth broad, TPM avg 8.5965 / max 1768.7421, expressed in 381 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115733	8.5965	381

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	97.07	gold quality
right coronary artery	UBERON:0001625	95.48	gold quality
synovial joint	UBERON:0002217	95.39	gold quality
lymph node	UBERON:0000029	94.34	gold quality
layer of synovial tissue	UBERON:0007616	94.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.99	gold quality
pericardium	UBERON:0002407	93.64	gold quality
omental fat pad	UBERON:0010414	93.17	gold quality
peritoneum	UBERON:0002358	93.13	gold quality
decidua	UBERON:0002450	92.91	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.08	gold quality
rectum	UBERON:0001052	92.07	gold quality
mucosa of stomach	UBERON:0001199	92.04	gold quality
smooth muscle tissue	UBERON:0001135	91.68	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.38	gold quality
placenta	UBERON:0001987	91.23	gold quality
olfactory bulb	UBERON:0002264	91.17	silver quality
right adrenal gland cortex	UBERON:0035827	90.45	gold quality
adipose tissue	UBERON:0001013	90.10	gold quality
triceps brachii	UBERON:0001509	89.86	gold quality
descending thoracic aorta	UBERON:0002345	89.86	gold quality
periodontal ligament	UBERON:0008266	89.71	gold quality
heart right ventricle	UBERON:0002080	89.60	gold quality
coronary artery	UBERON:0001621	89.54	gold quality
connective tissue	UBERON:0002384	89.40	gold quality
type B pancreatic cell	CL:0000169	89.13	gold quality
thoracic aorta	UBERON:0001515	89.06	gold quality
left coronary artery	UBERON:0001626	88.85	gold quality
ascending aorta	UBERON:0001496	88.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	1704.70
E-MTAB-8322	yes	1326.32
E-HCAD-10	yes	59.47
E-MTAB-6678	yes	40.02
E-ANND-3	yes	30.47
E-MTAB-10553	yes	28.45
E-CURD-112	yes	20.58
E-HCAD-9	yes	17.39
E-MTAB-10042	yes	9.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RARA, RARB, RARG, SP1

miRNA regulators (miRDB)

11 targeting FOLR2, 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-6721-5P	99.93	68.92	2981
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-215-3P	97.02	68.01	1209
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-6800-5P	94.59	64.80	525

Literature-anchored findings (GeneRIF, showing 29)

• FR-beta gene is a target for multiple coordinate actions of nuclear receptors for ATRA directly and indirectly acting on a transcriptional complex containing activating Sp1/ets and inhibitory AP-1 proteins. (PMID:12543860)
• study describes that functional FRbeta is specifically expressed by M-CSF-polarized (M2) macrophages as well as by ex vivo isolated tumor-associated macrophages, and that tumors induce its expression in an M-CSF-dependent manner (PMID:19951991)
• The rare alleles of specific single nucleotide polymorphisms within the FOLR1, FOLR2, and FOLR3 genes were statistically significant for association with meningomyelocele. (PMID:20683905)
• Expression of folate receptor-beta on activated macrophages holds a promising potential for early diagnosis of atherosclerosis. (Review) (PMID:22094710)
• Functional FR-beta present on osteoarthritis synovial macrophages provides a potential tool for the diagnosis and treatment of this disease. (PMID:22211358)
• High Folate Receptor beta expressing tumor-associated macrophages are associated with pancreatic cancer. (PMID:22350599)
• High FOLR2 mRNA expression is associated with uraemic patients on hemodialysis. (PMID:23439585)
• severe pre-eclampsia is associated with decreased placental expression of FR-beta and a reduction in the number of fetal macrophages (Hofbauer cells) (PMID:23480364)
• The FRalpha gene was expressed in all parathyroid cells analyzed, and the FRbeta gene was expressed by most. (PMID:24206618)
• FR-beta is uniquely expressed on this proinflammatory subpopulation offers a new strategy to suppress migration of inflammatory monocytes into sites of inflammation. (PMID:25015955)
• we confirmed the similarities between epithelial ovarian cancer and fallopian tube, normal and adenocarcinoma using FOLR1, FOLR2, CD68 and CD11b markers (PMID:25971554)
• FR-beta expression was low or absent in the majority of ovarian, breast and colorectal tumor samples. (PMID:26248049)
• Folate receptor beta as a novel CD11b/CD18 regulator for trafficking and homing of a subset of macrophages on collagen. (PMID:27534550)
• We identified eight novel variants in SLC19A1 and twelve novel variants in FOLR1, FOLR2, and FOLR3. Pathogenic variants include c.1265delG in SLC19A1 resulting in an early stop codon, four large insertion deletion variants in FOLR3, and a stop_gain variant in FOLR3 (PMID:28948692)
• Study report the expression of both FR-alpha and FR-beta on CD138 + plasma cells isolated from patients with multiple myeloma and the up-regulation of both FR-alpha and FR-beta expression after exposure to all-trans retinoic acid in two model myeloma cell lines. (PMID:29616859)
• we identified and characterised oncogenic fusion genes and their function in CRC, and implicated NAGLU-IKZF3 and RNF121-FOLR2 as novel molecular targets for personalised medicine development. (PMID:29955133)
• Folate receptor beta is expressed on myeloid cells and activated macrophages. FRbeta represents a useful marker for rheumatoid arthritis disease. [review] (PMID:30280318)
• Silencing of the expression of the FOLR2 gene in NCI-H1650 cells reduced cell viability, increased cell apoptosis, and arrested cells in the G1 phase of the cell cycle, decreased the expression of cyclin D1, upregulated expression of cell cycle inhibitors, p21 and p27, upregulated the expression of Bax/Bcl-2, and inhibited phosphorylation of AKT, mTOR, and S6K1. (PMID:30415267)
• (18)F-AzaFol for Detection of Folate Receptor-beta Positive Macrophages in Experimental Interstitial Lung Disease-A Proof-of-Concept Study. (PMID:31824505)
• Targeting folate receptor beta positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex. (PMID:32296026)
• Folate Receptor beta (FRbeta) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1. (PMID:32532019)
• Folate Receptor Beta as a Direct and Indirect Target for Antibody-Based Cancer Immunotherapy. (PMID:34070369)
• Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes. (PMID:34755134)
• Folate Receptor Beta for Macrophage Imaging in Rheumatoid Arthritis. (PMID:35185910)
• Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids. (PMID:35255727)
• FOLR2+ Macrophages Are Associated with T-cell Infiltration and Improved Prognosis. (PMID:35394484)
• Association of periconceptional folate supplements and FOLR1 and FOLR2 gene polymorphisms with risk of congenital heart disease in offspring: A hospital-based case-control study.", trans “FOLR1FOLR2. (PMID:35545363)
• Mutational analysis of FOLR1 and FOLR2 genes in children with Myelomeningocele. (PMID:37883728)
• microRNA-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation. (PMID:38166756)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	folr	ENSDARG00000102442
mus_musculus	Folr2	ENSMUSG00000032725
rattus_norvegicus	Folr2	ENSRNOG00000019890

Paralogs (4): FOLR1 (ENSG00000110195), FOLR3 (ENSG00000110203), RTBDN (ENSG00000132026), IZUMO1R (ENSG00000183560)

Protein

Protein identifiers

Folate receptor beta — P14207 (reviewed: P14207)

Alternative names: Folate receptor 2, Folate receptor, fetal/placental, Placental folate-binding protein

All UniProt accessions (9): E7EU04, P14207, F5GXV3, F5GZ45, F5H3Z4, F5H4Z6, F5H5L8, J3KQP4, J3KR13

UniProt curated annotations — full annotation on UniProt →

Function. Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. Expressed in placenta and hematopoietic cells. Expression is increased in malignant tissues.

Post-translational modifications. N-glycosylated.

Induction. Up-regulated by retinoic acid.

Similarity. Belongs to the folate receptor family.

RefSeq proteins (4): NP_000794, NP_001107006, NP_001107007, NP_001107008 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004269	Folate_rcpt	Family
IPR018143	Folate_rcpt-like	Domain

Pfam: PF03024

UniProt features (47 total): strand 10, helix 9, disulfide bond 8, sequence conflict 6, binding site 5, glycosylation site 2, turn 2, signal peptide 1, chain 1, sequence variant 1, propeptide 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4KMY	X-RAY DIFFRACTION	1.79
4KN0	X-RAY DIFFRACTION	2.1
4KMZ	X-RAY DIFFRACTION	2.3
4KN1	X-RAY DIFFRACTION	2.3
4KN2	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14207-F1	89.54	0.75

Functional residue map

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

Ligand- & substrate-binding residues (5): 97; 101; 118–122; 151–156; 190

Post-translational modifications (1): 230

Disulfide bonds (8): 31–59, 51–99, 60–103, 83–169, 90–140, 129–203, 133–183, 146–163

Glycosylation sites (2): 195, 115

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins
R-HSA-196757	Metabolism of folate and pterines

MSigDB gene sets: 191 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_SINGLE_FERTILIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, PEREZ_TP63_TARGETS, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, MODULE_64, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOCC_CELL_SURFACE, RIZKI_TUMOR_INVASIVENESS_3D_DN, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (7): inflammatory response (GO:0006954), cell adhesion (GO:0007155), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), positive regulation of cell population proliferation (GO:0008284), folic acid transport (GO:0015884), sperm-egg recognition (GO:0035036), cellular response to folic acid (GO:0071231)

GO Molecular Function (3): folic acid binding (GO:0005542), signaling receptor activity (GO:0038023), folic acid receptor activity (GO:0061714)

GO Cellular Component (6): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
single fertilization	2
membrane	2
defense response	1
cellular process	1
cellular process involved in reproduction in multicellular organism	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
dicarboxylic acid transport	1
vitamin transport	1
modified amino acid transport	1
cell-cell recognition	1
response to folic acid	1
cellular response to vitamin	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
vitamin binding	1
carboxylic acid binding	1
modified amino acid binding	1
heterocyclic compound binding	1
molecular transducer activity	1
folic acid binding	1
folic acid transport	1
cargo receptor activity	1
cellular response to folic acid	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

1460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOLR2	FOLH1	Q04609	783
FOLR2	SLC46A1	Q96NT5	777
FOLR2	PCBP1	Q15365	747
FOLR2	SLC19A1	P41440	699
FOLR2	EGFR	P00533	681
FOLR2	TFRC	P02786	659
FOLR2	FGF3	P11487	592
FOLR2	IZUMO1	Q8IYV9	587
FOLR2	MSLN	Q13421	581
FOLR2	EPCAM	P16422	577
FOLR2	ERBB2	P04626	546
FOLR2	DHFR	P00374	544
FOLR2	MUC1	P13931	544
FOLR2	FCGR3B	O75015	528
FOLR2	TYMS	P04818	515

IntAct

2 interactions, top by confidence:

A	B	Type	Score
FOLR3	FOLR2	psi-mi:“MI:0914”(association)	0.350

BioGRID (3): FOLR2 (Affinity Capture-MS), FOLR2 (Positive Genetic), FOLR2 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q1LRJ2, A6ND01, B8JI67, E1B9E5, F1M928, O15547, P02702, P02752, P0DJF3, P0DN42, P10820, P14207, P15328, P16229, P27767, P35846, P41439, P48251, P51653, P86009, Q05685, Q3HRV3, Q3S2X5, Q3UPR9, Q3V5L5, Q4TUC0, Q5EA85, Q5FB95, Q5M936, Q62178, Q62190, Q64663, Q64716, Q6DFV8, Q765H6, Q7TPG6, Q7Z5A8, Q8BMN4, Q8IVN8, Q8N2E2

Diamond homologs: A6ND01, F1M928, P02702, P02752, P14207, P15328, P35846, P41439, P86009, Q05685, Q9EQF4, Q5DRQ5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

821 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72220864:A:AG	acceptor_gain	1.0000
11:72220865:C:G	acceptor_gain	1.0000
11:72220865:CCCAG:C	acceptor_loss	1.0000
11:72220866:CCAGT:C	acceptor_loss	1.0000
11:72220867:CAGT:C	acceptor_loss	1.0000
11:72220868:A:AG	acceptor_gain	1.0000
11:72220868:A:T	acceptor_loss	1.0000
11:72220868:AGT:A	acceptor_gain	1.0000
11:72220869:G:A	acceptor_loss	1.0000
11:72220869:G:GA	acceptor_gain	1.0000
11:72220869:GT:G	acceptor_gain	1.0000
11:72220869:GTG:G	acceptor_gain	1.0000
11:72220869:GTGC:G	acceptor_gain	1.0000
11:72220869:GTGCA:G	acceptor_gain	1.0000
11:72221054:AGCAG:A	donor_loss	1.0000
11:72221055:GCAG:G	donor_gain	1.0000
11:72221056:CAG:C	donor_loss	1.0000
11:72221057:AGGT:A	donor_loss	1.0000
11:72221058:GGTAG:G	donor_loss	1.0000
11:72221059:G:A	donor_loss	1.0000
11:72221060:T:A	donor_loss	1.0000
11:72221173:CAGGT:C	acceptor_loss	1.0000
11:72221175:G:GA	acceptor_loss	1.0000
11:72218735:G:GG	donor_gain	0.9900
11:72218757:C:G	donor_gain	0.9900
11:72218762:G:GT	donor_gain	0.9900
11:72220780:GAGGA:G	donor_gain	0.9900
11:72220785:G:GG	donor_gain	0.9900
11:72220870:T:TA	acceptor_gain	0.9900
11:72221008:G:GT	donor_gain	0.9900

AlphaMissense

1708 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72221286:G:C	W150C	0.993
11:72221286:G:T	W150C	0.993
11:72221298:G:C	W154C	0.993
11:72221298:G:T	W154C	0.993
11:72220881:G:C	W54C	0.992
11:72220881:G:T	W54C	0.992
11:72221244:G:C	W136C	0.992
11:72221244:G:T	W136C	0.992
11:72221049:G:C	W110C	0.991
11:72221049:G:T	W110C	0.991
11:72221616:T:C	F208L	0.990
11:72221618:T:A	F208L	0.990
11:72221618:T:G	F208L	0.990
11:72221247:G:C	W137C	0.989
11:72221247:G:T	W137C	0.989
11:72221296:T:A	W154R	0.983
11:72221296:T:C	W154R	0.983
11:72221047:T:A	W110R	0.982
11:72221047:T:C	W110R	0.982
11:72221481:T:A	C163S	0.982
11:72221482:G:C	C163S	0.982
11:72220870:T:A	C51S	0.981
11:72220871:G:C	C51S	0.981
11:72220951:T:C	F78L	0.981
11:72220953:T:A	F78L	0.981
11:72220953:T:G	F78L	0.981
11:72221284:T:A	W150R	0.981
11:72221284:T:C	W150R	0.981
11:72220879:T:A	W54R	0.980
11:72220879:T:C	W54R	0.980

dbSNP variants (sampled 300 via entrez): RS1000342657 (11:72216359 T>G), RS1000723079 (11:72214984 T>C), RS1000842218 (11:72221125 C>T), RS1001131748 (11:72216522 A>C), RS1001296574 (11:72219917 A>T), RS1001311423 (11:72220140 G>A), RS1002851522 (11:72217925 A>G), RS1003373611 (11:72218202 C>T), RS1003513634 (11:72218243 A>C,G), RS1003595708 (11:72216801 G>A,C), RS1004405567 (11:72221821 G>C), RS1004525163 (11:72215570 TACGAAAAGCCAGTC>T), RS1004719119 (11:72215522 G>GAA), RS1005415738 (11:72217092 T>G), RS1006196833 (11:72216081 C>A,T)

Disease associations

OMIM: gene MIM:136425 | 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): CHEMBL5064 (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: 550,905 (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
CHEMBL225071	RALTITREXED	4	96,748
CHEMBL225072	PEMETREXED	4	55,761
CHEMBL34259	METHOTREXATE	4	398,396

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4S)-4-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-[4-[2-[2-[2-[[1-[2-[2-[4-[5-[7-chloro-8-[[(1R)-1-(5-cyano-2-fluorophenyl)ethyl]amino]-3-fluoro-6-methyl-1,5-naphthyridin-2-yl]pyrimidin-2-yl]piperazin-1-yl]-2-oxoethoxy]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethyl]piperazin-1-yl]-5-oxopentanoic acid	IC50	17 nM	US-20250127913: BIFUNCTIONAL FOLATE RECEPTOR BINDING COMPOUNDS

ChEMBL bioactivities

70 potent at pChembl≥5 of 70 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL3628346
9.80	IC50	0.16	nM	CHEMBL1834488
9.77	IC50	0.17	nM	CHEMBL1834488
9.72	IC50	0.19	nM	CHEMBL4445651
9.62	IC50	0.24	nM	CHEMBL4759798
9.47	IC50	0.34	nM	CHEMBL3628344
9.47	IC50	0.34	nM	CHEMBL4467936
9.37	IC50	0.43	nM	CHEMBL2158681
9.36	IC50	0.44	nM	CHEMBL4557278
9.35	IC50	0.45	nM	CHEMBL4553188
9.29	IC50	0.51	nM	CHEMBL4214638
9.28	IC50	0.53	nM	CHEMBL4471269
9.25	IC50	0.56	nM	CHEMBL4852455
9.24	IC50	0.58	nM	CHEMBL4214638
9.21	IC50	0.62	nM	CHEMBL4437824
9.14	IC50	0.72	nM	CHEMBL4761741
9.12	IC50	0.75	nM	CHEMBL4465095
9.03	IC50	0.93	nM	CHEMBL4441626
8.92	IC50	1.21	nM	CHEMBL4783397
8.82	IC50	1.5	nM	CHEMBL4866304
8.80	IC50	1.6	nM	CHEMBL4540298
8.80	IC50	1.57	nM	CHEMBL4444011
8.78	IC50	1.67	nM	CHEMBL4741259
8.76	IC50	1.75	nM	CHEMBL4790375
8.59	IC50	2.59	nM	CHEMBL4447805
8.59	IC50	2.6	nM	CHEMBL4789686
8.55	IC50	2.84	nM	CHEMBL4465095
8.51	IC50	3.11	nM	CHEMBL4445651
8.44	IC50	3.6	nM	CHEMBL3335605
8.41	IC50	3.87	nM	CHEMBL4538151
8.28	IC50	5.22	nM	CHEMBL4538151
8.25	IC50	5.6	nM	CHEMBL365307
8.25	IC50	5.6	nM	CHEMBL192632
8.25	IC50	5.63	nM	CHEMBL4755197
8.18	IC50	6.54	nM	CHEMBL4214638
8.12	IC50	7.57	nM	CHEMBL3628344
8.11	IC50	7.78	nM	CHEMBL4540298
7.94	IC50	11.6	nM	CHEMBL365307
7.91	IC50	12.2	nM	CHEMBL192632
7.76	IC50	17.5	nM	CHEMBL3628345
7.73	IC50	18.8	nM	CHEMBL4213181
7.70	IC50	20	nM	CHEMBL491104
7.66	IC50	22	nM	RALTITREXED
7.66	IC50	21.7	nM	CHEMBL4557278
7.52	IC50	30.2	nM	CHEMBL1834488
7.45	IC50	35.3	nM	CHEMBL2158681
7.43	IC50	37.41	nM	CHEMBL4205344
7.26	IC50	54.3	nM	CHEMBL3628347
7.22	IC50	60	nM	PEMETREXED
6.97	IC50	106	nM	METHOTREXATE

PubChem BioAssay actives

70 with measured affinity, of 148 total; 39 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)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1252415: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0001	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1164835: Inhibition of FRbeta (unknown origin) expressed in Chinese hamster D4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0002	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0002	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0002	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1252415: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0003	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylsulfanyl]benzoyl]amino]pentanedioic acid	1631981: Inhibition of human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0003	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0004	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluoropyridine-2-carbonyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0004	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-(2,2,2-trifluoroacetyl)amino]benzoyl]amino]pentanedioic acid	1631981: Inhibition of human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0004	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]pyridine-2-carbonyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0005	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-formylamino]benzoyl]amino]pentanedioic acid	1631981: Inhibition of human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0005	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylamino]benzoyl]amino]pentanedioic acid	1631981: Inhibition of human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0006	uM
(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-3-carboxy-1-[[(1R)-1-carboxy-2-sulfanylethyl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1763695: Displacement of [3H]-folic acid from FRbeta (unknown origin) expressed in mouse RAW264.7 cells after 1 hr	ic50	0.0006	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0007	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0008	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluorobenzoyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0009	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-3-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0012	uM
(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-3-carboxy-1-[[(2S)-3-carboxy-1-[[(1R)-1-carboxy-2-[2-[(1R,3R,8R,12S,13R,18E,20Z,24R,25S,26S)-5,13,25-trimethyl-11,17,22-trioxospiro[2,10,16,23-tetraoxatetracyclo[22.2.1.03,8.08,25]heptacosa-4,18,20-triene-26,2’-oxirane]-12-yl]oxycarbonyloxyethyldisulfanyl]ethyl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1763695: Displacement of [3H]-folic acid from FRbeta (unknown origin) expressed in mouse RAW264.7 cells after 1 hr	ic50	0.0015	uM
(2S)-2-[[4-[acetyl-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino]benzoyl]amino]pentanedioic acid	1631981: Inhibition of human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0016	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0016	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0017	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0018	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethoxy]benzoyl]amino]pentanedioic acid	1631981: Inhibition of human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0026	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]furan-2-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0026	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]hexanedioic acid	1164835: Inhibition of FRbeta (unknown origin) expressed in Chinese hamster D4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0036	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0039	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	1380199: Binding affinity to human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0056	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid	1512995: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0056	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0056	uM
(2S)-2-[[4-[3-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1252415: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0175	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]pyridine-2-carbonyl]amino]pentanedioic acid	1380199: Binding affinity to human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0188	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	1709475: Inhibition of human FRbeta expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0200	uM
(2S)-2-[[5-[methyl-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl]amino]thiophene-2-carbonyl]amino]pentanedioic acid	1164835: Inhibition of FRbeta (unknown origin) expressed in Chinese hamster D4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0220	uM
(2S)-2-[[6-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]pyridine-3-carbonyl]amino]pentanedioic acid	1380199: Binding affinity to human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0374	uM
(2S)-2-[[5-[3-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1252415: Binding affinity to human FRbeta expressed in Chinese hamster D4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0543	uM
Pemetrexed	1164835: Inhibition of FRbeta (unknown origin) expressed in Chinese hamster D4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0600	uM
Methotrexate	1164835: Inhibition of FRbeta (unknown origin) expressed in Chinese hamster D4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.1060	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]butanedioic acid	1164835: Inhibition of FRbeta (unknown origin) expressed in Chinese hamster D4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.3470	uM
(2S)-2-[[6-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]pyridine-3-carbonyl]amino]pentanedioic acid	1380199: Binding affinity to human FR-beta receptor expressed in Chinese hamster D4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.8391	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Folic Acid	affects binding, decreases reaction, increases response to substance, decreases expression	3
triphenyl phosphate	affects expression	1
trichostatin A	increases reaction, increases expression, affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
lometrexol	decreases reaction, increases response to substance	1
tebuconazole	decreases expression	1
romidepsin	increases expression, increases reaction	1
clothianidin	increases expression	1
N-((5-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-6-yl)propyl)thiophen-2-yl)carbonyl)glutamic acid	decreases reaction, increases response to substance, affects binding	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Cadmium	decreases expression	1
Cisplatin	decreases response to substance	1
Copper	affects cotreatment, increases expression	1
Endosulfan	increases expression	1
Tobacco Smoke Pollution	increases methylation	1
Tretinoin	increases expression, increases reaction, affects binding, decreases reaction	1
Valproic Acid	increases expression, increases reaction	1
Aflatoxin B1	increases methylation	1
Medroxyprogesterone Acetate	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

24 unique, capped per target: 24 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003025	Binding	Displacement of [3H]folic acid from human folate receptor beta in chinese hamster D4 cells assessed as relative binding affinity relative to folic acid	Synthesis and biological activity of a novel series of 6-substituted thieno[2,3-d]pyrimidine antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors over the reduced folate carrier and proton-coupled folate transporter for cellular entry. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1MJ	Abcam K-562 FOLR2 KO	Cancer cell line	Female
CVCL_D2J4	Abcam Raji FOLR2 KO	Cancer cell line	Male
CVCL_UQ51	Abcam Jurkat FOLR2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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