dimethyl itaconate   Click here for help

GtoPdb Ligand ID: 9939

Synonyms: dimethylitaconate | itaconic acid dimethyl ester
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Dimethyl itaconate is a membrane-permeable derivative of the immunoregulatory metabolite itaconate. Itaconate is one of the most highly induced metabolites produced when activated macrophages undergo metabolic remodeling. Itaconate acts as a major physiological regulator of metabolic switching and effector functions of inflammatory macrophages. Itaconate and dimethyl itaconate inhibit production of IL-6 and IL-12 (secondary transcriptional response), but not TNF (a primary transcriptional response) following Toll-like receptor stimulation [4].

Itaconate has been found to promote an electrophilic stress response (i.e. a rapid adaptive defense response) [1]. An electrophilic stress response involves various mechanisms, including the nuclear translocation of the redox-sensitive transcription factor Nrf2 (nuclear factor E2-related factor 2), which senses electrophilic and oxidative stresses and protects against cellular damage via Kelch-like ECH-associated protein 1 (Keap1) [2-3,5]. Both itaconate and dimethyl itaconate induce Nrf2-dependent and -independent responses, the Nrf2-independent response being that which involves regulation of IκBζ [1].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 4
Hydrogen bond donors 0
Rotatable bonds 5
Topological polar surface area 52.6
Molecular weight 158.06
XLogP 0.24
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES COC(=O)CC(=C)C(=O)OC
Isomeric SMILES COC(=O)CC(=C)C(=O)OC
InChI InChI=1S/C7H10O4/c1-5(7(9)11-3)4-6(8)10-2/h1,4H2,2-3H3
InChI Key ZWWQRMFIZFPUAA-UHFFFAOYSA-N
References
1. Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH et al.. (2018)
Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.
Nature, 556 (7702): 501-504. [PMID:29670287]
2. Dinkova-Kostova AT, Holtzclaw WD, Kensler TW. (2005)
The role of Keap1 in cellular protective responses.
Chem Res Toxicol, 18 (12): 1779-91. [PMID:16359168]
3. Itoh K, Tong KI, Yamamoto M. (2004)
Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles.
Free Radic Biol Med, 36 (10): 1208-13. [PMID:15110385]
4. Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, Cervantes-Barragan L, Ma X, Huang SC, Griss T et al.. (2016)
Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.
Cell Metab, 24 (1): 158-66. [PMID:27374498]
5. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P. (2004)
Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers.
Proc Natl Acad Sci USA, 101 (7): 2040-5. [PMID:14764894]