Target Information

Target General Information

Target ID

T83386 (Former ID: TTDI01918)

Target Name

Folate receptor alpha (FOLR1)

Synonyms

Ovarian tumorassociated antigen MOv18; KB cells FBP; Folate receptor, adult; Folate receptor 1; FRalpha; FOLR1; Adult folatebinding protein

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Gene Name

FOLR1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Malaria [ICD-11: 1F40-1F45]

Ovarian cancer [ICD-11: 2C73]

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 pHafter receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for normal embryonic development and normal cell proliferation.

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BioChemical Class

Folate receptor

UniProt ID

FOLR1_HUMAN

Sequence

MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPW
RKNACCSTNTSQEAHKDVSYLYRFNWNHCGEMAPACKRHFIQDTCLYECSPNLGPWIQQV
DQSWRKERVLNVPLCKEDCEQWWEDCRTSYTCKSNWHKGWNWTSGFNKCAVGAACQPFHF
YFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEVARFYAAAMSGAGPWA
AWPFLLSLALMLLWLLS

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Mirvetuximab soravtansine

Drug Info

Approved

Ovarian cancer

[2]

Pyrimethamine

Drug Info

Approved

Malaria

[3], [4]

Clinical Trial Drug(s)

[+] 10 Clinical Trial Drugs

EC20

Drug Info

Phase 3

Ovarian cancer

[5]

Farletuzumab

Drug Info

Phase 3

Ovarian cancer

[6]

MK-8109

Drug Info

Phase 3

Ovarian cancer

[7]

EC-145

Drug Info

Phase 2

Solid tumour/cancer

[8]

FolateImmune

Drug Info

Phase 2

Renal cell carcinoma

[9]

BMS-753493

Drug Info

Phase 1/2

Solid tumour/cancer

[10], [11]

Talotrexin

Drug Info

Phase 1/2

Solid tumour/cancer

[12]

EC0489

Drug Info

Phase 1

Solid tumour/cancer

[13]

IMGN-853

Drug Info

Phase 1

Solid tumour/cancer

[14]

STRO-002

Drug Info

Phase 1

Ovarian cancer

[15]

Mode of Action

[+] 3 Modes of Action

Antagonist

[+] 2 Antagonist drugs

Mirvetuximab soravtansine

Drug Info

[16]

Talotrexin

Drug Info

[23]

Modulator

[+] 8 Modulator drugs

Pyrimethamine

Drug Info

[1]

EC20

Drug Info

[17]

Farletuzumab

Drug Info

[18]

MK-8109

Drug Info

[19]

EC-145

Drug Info

[20]

FolateImmune

Drug Info

[21]

BMS-753493

Drug Info

[22]

EC0489

Drug Info

[24]

Inhibitor

[+] 1 Inhibitor drugs

IMGN-853

Drug Info

[25]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Folic acid

Ligand Info

Structure Description

Crystal structure of human folate receptor alpha in complex with folic acid

PDB:4LRH

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

[27]

PDB Sequence

RTELLNVCMN

¹⁷

AKHHKEKPGP

²⁷

EDKLHEQCRP

³⁷

WRKNACCSTN

⁴⁷

TSQEAHKDVS

⁵⁷

YLYRFNWNHC

⁶⁷

GEMAPACKRH

⁷⁷

FIQDTCLYEC

⁸⁷

SPNLGPWIQQ

⁹⁷

VDQSWRKERV

¹⁰⁷

LNVPLCKEDC

¹¹⁷

EQWWEDCRTS

¹²⁷

YTCKSNWHKG

¹³⁷

WNWTSGFNKC

¹⁴⁷

AVGAACQPFH

¹⁵⁷

FYFPTPTVLC

¹⁶⁷

NEIWTHSYKV

¹⁷⁷

SNYSRGSGRC

¹⁸⁷

IQMWFDPAQG

¹⁹⁷

NPNEEVARFY

²⁰⁷

AAAMSGT

Residue

Distance (Å)

TYR60

3.600

PHE62

4.342

ASP81

2.626

THR82

4.582

TYR85

3.659

GLN100

3.346

SER101

3.554

TRP102

2.902

ARG103

3.149

ARG106

3.131

Residue

Distance (Å)

VAL107

4.960

TRP134

3.375

HIS135

2.873

LYS136

3.266

GLY137

3.500

TRP138

3.278

TRP140

2.823

TRP171

3.440

SER174

2.870

TYR175

3.544

Ligand Name: N-(4-{[2-(2-Amino-4-Oxo-4,7-Dihydro-3h-Pyrrolo[2,3-D]pyrimidin-6-Yl)ethyl]amino}benzene-1-Carbonyl)-L-Glutamic Acid

Ligand Info

Structure Description

Crystal structure of human folate receptor alpha in complex with novel antifolate AGF183

PDB:5IZQ

Method

X-ray diffraction

Resolution

3.60 Å

Mutation

[28]

PDB Sequence

RTELLNVCMN

¹⁷

AKHHKEKPGP

²⁷

EDKLHEQCRP

³⁷

WRKNACCSTN

⁴⁷

TSQEAHKDVS

⁵⁷

YLYRFNWNHC

⁶⁷

GEMAPACKRH

⁷⁷

FIQDTCLYEC

⁸⁷

SPNLGPWIQQ

⁹⁷

VDQSWRKERV

¹⁰⁷

LNVPLCKEDC

¹¹⁷

EQWWEDCRTS

¹²⁷

YTCKSNWHKG

¹³⁷

WNWTSGFNKC

¹⁴⁷

AVGAACQPFH

¹⁵⁷

FYFPTPTVLC

¹⁶⁷

NEIWTHSYKV

¹⁷⁷

SNYSRGSGRC

¹⁸⁷

IQMWFDPAQG

¹⁹⁷

NPNEEVARFY

²⁰⁷

AAAMSGT

Residue

Distance (Å)

TYR60

3.781

PHE62

4.074

ASP81

2.862

TYR85

3.506

GLN100

3.677

SER101

3.827

TRP102

3.201

ARG103

2.915

ARG106

2.762

VAL107

4.483

Residue

Distance (Å)

TRP134

3.314

HIS135

2.786

LYS136

2.954

GLY137

2.870

TRP138

2.958

TRP140

2.892

TRP171

3.237

SER174

2.674

TYR175

3.558

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Endocytosis	hsa04144	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 1 KEGG Pathways

Endocytosis

Reactome

[+] 2 Reactome Pathways

COPII (Coat Protein 2) Mediated Vesicle Transport

Cargo concentration in the ER

WikiPathways

[+] 1 WikiPathways

Folate Metabolism

References

Top

REF 1

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 2

FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 761310.

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4800).

REF 4

How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020691)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022740)

REF 7

Clinical pipeline report, company report or official report of Endocyte.

REF 8

ClinicalTrials.gov (NCT00507741) Study of Vintafolide (MK-8109, EC145) in Participants With Advanced Ovarian and Endometrial Cancers (MK-8109-007, EC-FV-02). U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT01511055) Intra-op Detection of Occult Ovarian Carcinoma Using a Folate-Alpha Receptor Specific Fluorescent Ligand. U.S. National Institutes of Health.

REF 10

REF 11

ClinicalTrials.gov (NCT00550017) A Phase 1/2 Study of Epofolate (BMS-753493) in Subjects With Advanced Cancer (Schedule 2). U.S. National Institutes of Health.

REF 12

ClinicalTrials.gov (NCT00112060) A Study to Assess the Safety and Preliminary Efficacy of PT-523 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC). U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT00852189) Study of EC0489 for the Treatment of Refractory or Metastatic Tumors. U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT01609556) First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of IMGN853 in Adults With Ovarian Cancer and Other FOLR1-Positive Solid Tumors. U.S. National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT03748186) Study of STRO-002, an Anti-Folate Receptor Alpha (FolRalpha) Antibody Drug Conjugate in Ovarian & Endometrial Cancers. U.S. National Institutes of Health.

REF 16

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 17

EP patent application no. 2822386, Folate receptor alpha binding ligands.

REF 18

Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer.Gynecol Oncol.2013 Jun;129(3):452-8.

REF 19

A current review of folate receptor alpha as a potential tumor target in non-small-cell lung cancer. Drug Des Devel Ther. 2015; 9: 4989-4996.

REF 20

Significance of Folate Receptor alpha and Thymidylate Synthase Protein Expression in Patients with Non-Small Cell Lung Cancer treated with Pemetrexed. J Thorac Oncol. 2013 January; 8(1): 19-30.

REF 21

Responsiveness of the Effective Consumer Scale (EC-17). J Rheumatol. 2009 Sep;36(9):2087-91.

REF 22

A phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493), a folate receptor targeted chemotherapeutic agent in humans with advanced solid tumors. Invest New Drugs. 2015 Apr;33(2):321-31.

REF 23

Cancer chemotherapy: targeting folic acid synthesis. Cancer Manag Res. 2010; 2: 293-301.

REF 24

National Cancer Institute Drug Dictionary (drug id 638649).

REF 25

Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconjug Chem. 2010 Jan;21(1):84-92.

REF 26

Clinical pipeline report, company report or official report of Sutro Biopharma.

REF 27

Structural basis for molecular recognition of folic acid by folate receptors. Nature. 2013 Aug 22;500(7463):486-9.

REF 28

Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor Alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis. J Med Chem. 2016 Sep 8;59(17):7856-76.

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