Top ▲

Ecto-5'-Nucleotidase

Click here for help

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1232

Nomenclature: Ecto-5'-Nucleotidase

Abbreviated Name: NT5E

Systematic Nomenclature: CD73

Family: Adenosine turnover

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 574 6q14.3 NT5E 5'-nucleotidase ecto
Mouse - 576 9 E3.1 Nt5e 5' nucleotidase, ecto
Rat - 576 8q31 Nt5e 5' nucleotidase, ecto
Previous and Unofficial Names Click here for help
eN | eNT | NT5 | 5' nucleotidase (CD73) | ecto-5'-nucleotidase | 5'-nucleotidase, ecto (CD73) | 5' nucleotidase, ecto | 5' nucleotidase | 5' nucleotidase, ecto
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
SynPHARM
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 3.1.3.5
Rank order of affinity (Human)
adenosine 5'-monophosphate, 5'-GMP, 5'-inosine monophosphate, 5'-UMP > 5'-dAMP, 5'-dGMP

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AB680 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 11.3 pKi 5
pKi 11.3 (Ki 5x10-12 M) [5]
compound 15 [PMID: 32045236] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.4 – 8.5 pKi 4
pKi 8.5 (Ki 3.33x10-9 M) [4]
Description: Inhibition of CD73 in human MDA-MB-231 cancer cells.
pKi 8.4 (Ki 3.59x10-9 M) [4]
Description: Ki vs. soluble human CD73 in vitro.
compound 15 [PMID: 32045236] Small molecule or natural product Immunopharmacology Ligand Rn Inhibition 7.8 pKi 4
pKi 7.8 (Ki 1.51x10-8 M) [4]
Description: Ki vs. soluble rat CD73 in vitro.
PSB-0963 Small molecule or natural product Rn Inhibition 6.8 pKi 2
pKi 6.8 (Ki 1.5x10-7 M) [2]
View species-specific inhibitor tables
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
oleclumab Peptide Primary target of this compound Immunopharmacology Ligand Hs Binding 11.4 pKd 6
pKd 11.4 (Kd 4.2x10-12 M) [6]
Immunopharmacology Comments
Via the conversion of ADP/ATP to AMP (CD39; ENTPD1) and AMP to adenosine (CD73; NT5E) these ectonucleotidase enzymes are crucial to the regulation of purinergic signals delivered to immune cells [1]. Increased adenosine levels are reported in tumours, and drives a shift to an anti-inflammatory environment which can promote tumour growth [14]. Increasing evidence validates both of these enzymes as potential druggable targets in cancer [3,7,12].
CD73 is immunosuppressive and pro-metastatic. CD73 on tumour cells, increases extracellular adenosine levels which inhibits the function of tumour-reactive CD8+ cells via A2A adenosine receptors, and enhances tumour cell invasion and chemotaxis (the latter via A2B adenosine receptors) [12].

Anti-CD73 mAbs that target this adenosine-driven immunosuppressive pathway are being expolited for their potential to promote anti-tumour immune responses across a wide range of tumours. Bristol-Myers Squibb, MedImmune and Innate Pharma (preclinical) have ongoing anti-CD73 immuno-oncology programmes (September 2017).
Examples of clinical evaluations of anti-CD73 mAbs in patients with advanced solid tumours: MedImmune's oleclumab (MEDI9447) is being evaluated alone and in combination with anti PD-L1 mAb durvalumab (MEDI4736) in Phase 1 clinical trial NCT02503774. Bristol-Myers' BMS-986179 is being tested in combination with the anti-PD-1 mAb nivolumab (BMS-936558) in Phase 1/2 trial NCT02754141.
SARS-CoV-2 and COVID-19: Corvus Pharmaceuticals have an agonistic (immunostimulatory) CD73-targeting mAb (CPI-006; developed as an immuno-oncology agent) that is able to promote B cell activation, lymphocyte trafficking (and production of antigen-specific IgM and IgG antibodies), and to elevate numbers of memory B cells. CPI-006 is being repositioned as a novel immunotherapy approach that is predicted to provide both immediate (e.g. shortened recovery time) and long-term (e.g. improved protective immunity) clinical benefits for COVID-19 patients (Phase 1 clinical trial NCT04464395).
Immuno Process Associations
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0007159 leukocyte cell-cell adhesion IDA
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0050728 negative regulation of inflammatory response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0050728 negative regulation of inflammatory response IEA
General Comments
CD73 is membrane-bound extracellular enzyme that, together with CD39, plays a major role in promoting immunosuppression through the pathway that degrades adenosine triphosphate (ATP) into adenosine. CD73 performs the terminal catalytic step in conversion to adenosine. It is overexpressed in several cancer types, and this has been linked with poor prognosis in certain cancers [8-11,13,15]. Adenosine accumulation driven by this pathway in the tumour microenvironment causes immune suppression, is pro-angiogenic and stimulates tumour metastasis.

References

Show »

1. Antonioli L, Pacher P, Vizi ES, Haskó G. (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med, 19 (6): 355-67. [PMID:23601906]

2. Baqi Y, Lee SY, Iqbal J, Ripphausen P, Lehr A, Scheiff AB, Zimmermann H, Bajorath J, Müller CE. (2010) Development of potent and selective inhibitors of ecto-5'-nucleotidase based on an anthraquinone scaffold. J Med Chem, 53 (5): 2076-86. [PMID:20146483]

3. Bastid J, Cottalorda-Regairaz A, Alberici G, Bonnefoy N, Eliaou JF, Bensussan A. (2013) ENTPD1/CD39 is a promising therapeutic target in oncology. Oncogene, 32 (14): 1743-51. [PMID:22751118]

4. Bhattarai S, Pippel J, Scaletti E, Idris R, Freundlieb M, Rolshoven G, Renn C, Lee SY, Abdelrahman A, Zimmermann H et al.. (2020) 2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes. J Med Chem, 63 (6): 2941-2957. [PMID:32045236]

5. Bowman CE, da Silva RG, Pham A, Young SW. (2019) An Exceptionally Potent Inhibitor of Human CD73. Biochemistry, 58 (31): 3331-3334. [PMID:31334635]

6. Geoghegan JC, Diedrich G, Lu X, Rosenthal K, Sachsenmeier KF, Wu H, Dall'Acqua WF, Damschroder MM. (2016) Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action. MAbs, 8 (3): 454-67. [PMID:26854859]

7. Häusler SF, Del Barrio IM, Diessner J, Stein RG, Strohschein J, Hönig A, Dietl J, Wischhusen J. (2014) Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion. Am J Transl Res, 6 (2): 129-39. [PMID:24489992]

8. Leclerc BG, Charlebois R, Chouinard G, Allard B, Pommey S, Saad F, Stagg J. (2016) CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer. Clin Cancer Res, 22 (1): 158-66. [PMID:26253870]

9. Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, Stagg J. (2013) CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci USA, 110 (27): 11091-6. [PMID:23776241]

10. Lu XX, Chen YT, Feng B, Mao XB, Yu B, Chu XY. (2013) Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma. World J Gastroenterol, 19 (12): 1912-8. [PMID:23569336]

11. Ren ZH, Lin CZ, Cao W, Yang R, Lu W, Liu ZQ, Chen YM, Yang X, Tian Z, Wang LZ et al.. (2016) CD73 is associated with poor prognosis in HNSCC. Oncotarget, 7 (38): 61690-61702. [PMID:27557512]

12. Stagg J. (2012) The double-edge sword effect of anti-CD73 cancer therapy. Oncoimmunology, 1 (2): 217-218. [PMID:22720247]

13. Wang H, Lee S, Nigro CL, Lattanzio L, Merlano M, Monteverde M, Matin R, Purdie K, Mladkova N, Bergamaschi D et al.. (2012) NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br J Cancer, 106 (8): 1446-52. [PMID:22454080]

14. Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B. (2011) CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest, 121 (6): 2371-82. [PMID:21537079]

15. Wu XR, He XS, Chen YF, Yuan RX, Zeng Y, Lian L, Zou YF, Lan N, Wu XJ, Lan P. (2012) High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol, 106 (2): 130-7. [PMID:22287455]

Contributors

Show »

How to cite this page