Cyclic GMP-AMP turnover

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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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cGAS acts as a pattern recognition sensor for cytosolic DNA. Its synthetic product cGAMP activates STING, which induces the interferon response, and production of inflammatory cytokines.

Enzymes

3312

Targets of relevance to immunopharmacology are highlighted in blue

cyclic GMP-AMP synthase Show summary »« Hide summary More detailed page go icon to follow link

ectonucleotide pyrophosphatase/phosphodiesterase 1 Show summary »« Hide summary

Target Id

3312

Nomenclature

ectonucleotide pyrophosphatase/phosphodiesterase 1

Previous and unofficial names

M6S1 | NPPS | PDNP1

Genes

ENPP1 (Hs), Enpp1 (Mm), Enpp1 (Rn)

Ensembl ID

ENSG00000197594 (Hs), ENSMUSG00000037370 (Mm), ENSRNOG00000013994 (Rn)

UniProtKB AC

P22413 (Hs), P06802 (Mm), ENPP1_RAT (Rn)

EC number

3.1.4.1

3.6.1.9

Inhibitors

ISM5939 pIC₅₀ 9.4 [4]

ENPP1 inhibitor 27 pIC₅₀ 8.9 [2]

ENPP1 inhibitor 29f pIC₅₀ 7.2 [1]

Comment

ENPP1 is one of seven mammalian genes that encode enzymes with ectonucleotidase/nucleotide phosphohydrolase activities. Members of the family are highly conserved at the protein level, with differential expression patterns that underlie their regulatory roles in physiological and pathological processes. ENPP1 hydrolyzes STING-activating cyclic GMP-AMP (cGAMP). Selective ENPP1 inhibition is proposed as a mechanism to elevate extracellular cGAMP in the tumour microenvironment, as an alternative to direct STING agonist-mediated induction of the immune response against cancer [3-5].

Comments

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References

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1. Cho Y, Kang M, Ji SH, Jeong HJ, Jung JE, Oh DH, Park S, Park YY, Choi J, Kim S et al.. (2023) Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy. J Med Chem, 66 (22): 15141-15170. [PMID:37963811]

2. Gao S, Hou Y, Xu Y, Li J, Zhang C, Jiang S, Yu S, Liu L, Tu W, Yu B et al.. (2024) Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment. Eur J Med Chem, 279: 116853. [PMID:39270452]

3. Onyedibe KI, Wang M, Sintim HO. (2019) ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors-A STING in the Tale of ENPP1. Molecules, 24 (22). [PMID:31752288]

4. Pu C, Cui H, Yu H, Cheng X, Zhang M, Qin L, Ning Z, Zhang W, Chen S, Qian Y et al.. (2025) Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors. Nat Commun, 16 (1): 4793. [PMID:40410143]

5. Ruiz-Fernández de Córdoba B, Martínez-Monge R, Lecanda F. (2023) ENPP1 Immunobiology as a Therapeutic Target. Clin Cancer Res, 29 (12): 2184-2193. [PMID:36719675]

6. Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K et al.. (2017) Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun, 8 (1): 750. [PMID:28963528]

7. Zhou W, Whiteley AT, de Oliveira Mann CC, Morehouse BR, Nowak RP, Fischer ES, Gray NS, Mekalanos JJ, Kranzusch PJ. (2018) Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance. Cell, 174 (2): 300-311.e11. [PMID:30007416]

How to cite this family page

Database page citation:

Cyclic GMP-AMP turnover. Accessed on 19/06/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1049.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.