Drug Information

Drug (ID: DG01074) and It's Reported Resistant Information

• Name: Epalrestat
• Synonyms: Epalrestat; 82159-09-9; Kinedak; Epalrestatum; Ono 2235; Ono-2235; ONO-2; 2-((z)-5-((e)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid; UNII-424DV0807X; C15H13NO3S2; 2-[(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid; CHEMBL56337; 5-((1Z,2E)-2-Methyl-3-phenylpropenylidene)-4-oxo-2-thioxo-3-thiazolidineacetic acid; CHEBI:31539; ONO2235; 5-((Z,E)-beta-Methylcinnamylidene)-4-oxo-2-thioxo-3-thiazolidineacetic acid; MFCD00865484; 424DV0807X; {(5Z)-5-[(2E)-2-methyl-3-phenylprop-2-en-1-ylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl}acetic acid; Epalrestat [INN]; Epalrestatum [Latin]; {5-[(E)-2-Methyl-3-phenyl-prop-2-en-(Z)-ylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid; 2-[(5Z)-5-[(2E)-2-methyl-3-phenylprop-2-en-1-ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid; ONO 2; Kinedak (TN); Aldonil; Aldorin; Tanglin; NCGC00164613-01; Epalrestat- Bio-X; 5-[(1Z, 2E)-2-methyl-3-phenylpropenylidene]-4-oxo2-thioxo-3-thiazolidineacetic acid; Epalrestat (JP17/INN); 3-Thiazolidineacetic acid, 5-(2-methyl-3-phenyl-2-propenylidene)-4-oxo-2-thioxo-, (E,E)-; SCHEMBL49049; MLS000806985; GTPL11371; REGID_for_CID_1549120; HMS2747M09; HMS3887A17; ZINC1533688; BBL029067; BDBM50049730; s2035; STK337187; AKOS000274207; BCP9000649; CCG-267693; DB15293; NCGC00164613-08; NCGC00164613-12; AS-13345; BE164412; H951; HY-66009; SMR000414799; BCP0726000053; E0906; SW219826-1; D01688; AB00647195_06; 159E099; Q5382029; [5-(2-Methyl-3-phenyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid; 2-(5-(2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid; (5-[(e)-2-methyl-3-phenyl-prop-2-en-(z)-ylidene]-4-oxo-2-thioxo-thiazolidin-3-yl)-acetic acid 82159-; {(5Z)-5-[(2E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl}acetic acid; 2-[(5Z)-5-[(E)-3-phenil-2-methylprop-2-enylidene]-4-oxo-2-thioxo-3-thiazolidinyl]acetic acid
• Indication:
  In total 2 Indication(s)
  Diabetic neuropathy [ICD-11: 8C0Z]; Approved; [1]
  Pain [ICD-11: MG30]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Lung cancer [ICD-11: 2C25]; [1]
• Target: Aldose reductase (AKR1B1); ALDR_HUMAN; [1]
• Target: Voltage-gated L-type calcium channel (L-CaC); NOUNIPROTAC; [1]
• Formula: C15H13NO3S2
• IsoSMILES: C/C(=C\\C1=CC=CC=C1)/C=C\\2/C(=O)N(C(=S)S2)CC(=O)O
• InChI: 1S/C15H13NO3S2/c1-10(7-11-5-3-2-4-6-11)8-12-14(19)16(9-13(17)18)15(20)21-12/h2-8H,9H2,1H3,(H,17,18)/b10-7+,12-8-
• InChIKey: CHNUOJQWGUIOLD-NFZZJPOKSA-N
• PubChem CID: 1549120
• ChEBI ID: CHEBI:31539
• TTD Drug ID: D03KOZ
• DrugBank ID: DB15293

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Aldo-keto reductase family 1 member B (AKR1B1) [1]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Function; Inhibition
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis strain; 1773
• In Vitro Model: Escherichia coli strain; 562
• In Vivo Model: Xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Coimmunoprecipitation assay; Immunofluorescence staining assay; High-content imaging analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK-8 assay; Colony formation assay
• Mechanism Description: Up-regulation of AKR1B1 led to enhanced glutathione synthesis and resistance to EGFR inhibitors in cell lines and xenograft mouse models. In addition, the antidiabetic drug epalrestat inhibited AKR1B1 and restored sensitivity to EGFR TKIs in patient-derived xenograft tumors.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aldo-keto reductase family 1 member B10 (AKR1B10) [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; .
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: MU375/MU383 patient-derived tumor organoids; Homo sapiens
• Experiment for Molecule Alteration: qPCR; IHC assay
• Experiment for Drug Resistance: Drug sensitivity testing
• Mechanism Description: Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.

References

• Ref 1: Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer .Sci Transl Med. 2021 Oct 6;13(614):eabg6428. doi: 10.1126/scitranslmed.abg6428. Epub 2021 Oct 6. 10.1126/scitranslmed.abg6428
• Ref 2: Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non-Small Cell Lung Cancer Patient-Derived Tumor Organoids. Clin Cancer Res. 2024 Sep 3;30(17):3855-3867.