Drug Information

Drug (ID: DG00551) and It's Reported Resistant Information

• Name: Leflunomide
• Synonyms: Leflunomide; 75706-12-6; Arava; lefunamide; Leflunomida; Leflunomidum; 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide; HWA 486; Leflunomidum [INN-Latin]; HWA-486; Repso; SU101; Arava (TN); 5-methyl-N-(4-(trifluoromethyl)phenyl)isoxazole-4-carboxamide; 5-Methyl-N-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamide; 5-Methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide; 4-Isoxazolecarboxamide, 5-methyl-N-[4-(trifluoromethyl)phenyl]-; alpha,alpha,alpha-Trifluoro-5-methyl-4-isoxazolecarboxy-p-toluidide; UNII-G162GK9U4W; SU-101; 5-methyl-N-[4-(trifluoromethyl)phenyl]isoxazole-4-carboxamide; RS-34821; CHEMBL960; MLS000069648; CHEBI:6402; G162GK9U4W; 5-Methylisoxazole-4-(4-trifluoromethylcarboxanilide); MFCD00867593; NSC-677411; NSC-759864; NCGC00015610-02; SMR000058209; 5-methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide; 4-Isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-; CAS-75706-12-6; leflunomide medac; DSSTox_CID_3201; DSSTox_RID_76923; DSSTox_GSID_23201; Leflunomida [INN-Spanish]; SU 101 (pharmaceutical); Lefunomide [Inn-Spanish]; HSDB 7289; SR-01000000191; Arabloc; HWA486; Leflunomide teva; N-(4'-Trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide; L04AA13; Prestwick_87; Leflunomide [USAN:USP:INN:BAN]; Leflunomide winthrop; SU 101; SULOL; Leflunomide ratiopharm; Spectrum_000322; Opera_ID_1709; Prestwick0_000772; Prestwick1_000772; Prestwick2_000772; Prestwick3_000772; Spectrum5_000850; Lopac-L-5025; L 5025; SCHEMBL5057; BIDD:PXR0189; Lopac0_000649; BSPBio_000844; KBioSS_000802; Leflunomide, Immunosuppressant; MLS001076267; DivK1c_000916; Leflunomide (JAN/USP/INN); SPECTRUM1503927; 5-Methylisoxazole-4-(4-trifluoromethyl)carboxanilide; SPBio_002783; BPBio1_000930; GTPL6825; ZINC4840; DTXSID9023201; HMS502N18; KBio1_000916; KBio2_000802; KBio2_003370; KBio2_005938; AOB5964; NINDS_000916; 4-Isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl; HMS1570K06; HMS1922M06; HMS2090O12; HMS2097K06; HMS2235C07; HMS3262A19; HMS3268D12; HMS3371F21; HMS3414P03; HMS3654F07; HMS3673M17; HMS3678N21; HMS3714K06; HMS3865I13; Pharmakon1600-01503927; ALBB-019233; BCP22241; HY-B0083; Tox21_110182; Tox21_301873; Tox21_500649; BDBM50054601; DL-433; NSC677411; NSC759864; s1247; STL426823; AKOS000265193; Tox21_110182_1; AC-6796; BCP9000846; CCG-204736; CS-1781; DB01097; KS-1076; LP00649; MCULE-9490869974; NSC 677411; NSC 759864; SB17287; SDCCGSBI-0050629.P003; IDI1_000916; NCGC00015610-01; NCGC00015610-03; NCGC00015610-04; NCGC00015610-05; NCGC00015610-06; NCGC00015610-07; NCGC00015610-08; NCGC00015610-09; NCGC00015610-10; NCGC00015610-11; NCGC00015610-12; NCGC00015610-13; NCGC00015610-14; NCGC00015610-17; NCGC00015610-18; NCGC00015610-30; NCGC00022625-03; NCGC00022625-04; NCGC00022625-05; NCGC00022625-06; NCGC00022625-07; NCGC00022625-08; NCGC00255370-01; NCGC00261334-01; BM164612; H527; Leflunomide 100 microg/mL in Acetonitrile; A9622; AB00052389; EU-0100649; FT-0621959; L0250; SW196399-3; C07905; D00749; MLS-0003109.0001; AB00052389-17; AB00052389-18; AB00052389_19; AB00052389_21; 706L126; Q248550; Q-201289; SR-01000000191-2; SR-01000000191-4; SR-01000000191-7; BRD-K78692225-001-03-9; BRD-K78692225-001-11-2; 5-methyl-4-(4-trifluoromethyl-phenyl)aminocarbonylisoxazole; 5-methyl-4-(4-trifluoromethylphenyl)aminocarbonylisoxazole; Leflunomide, European Pharmacopoeia (EP) Reference Standard; N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide; 5-Methyl-N-[4-(trifluoromethyl)-phenyl]isoxazole-4-carboxamide; 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)-anilide; N-(4-trifluoromethylphenyl)-5-methylisoxa-zole-4-carboxamide; Isoxazole-4-carboxamide, 5-methyl-N-[4-(trifluoromethyl)phenyl]-; Leflunomide, United States Pharmacopeia (USP) Reference Standard; 5-methyl-N-(4-(trifluoromethyl)phenyl)isoxazole-4-carboxamide;Leflunomide; HWA486; RS-34821; SU101;HWA 486; RS 34821; SU 101; Leflunomide, Pharmaceutical Secondary Standard; Certified Reference Material; Leflunomide for peak identification, European Pharmacopoeia (EP) Reference Standard
• Indication:
  In total 2 Indication(s)
  Arthritis [ICD-11: FA20]; Approved; [1]
  Multiple sclerosis [ICD-11: 8A40]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Rheumatoid arthritis [ICD-11: FA20]; [1]
• Target: Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase); PYRD_PLAF7; [1]
• Formula: C12H9F3N2O2
• IsoSMILES: CC1=C(C=NO1)C(=O)NC2=CC=C(C=C2)C(F)(F)F
• InChI: 1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
• InChIKey: VHOGYURTWQBHIL-UHFFFAOYSA-N
• PubChem CID: 3899
• ChEBI ID: CHEBI:6402
• TTD Drug ID: D08ROP
• VARIDT ID: DR00130
• INTEDE ID: DR0921
• DrugBank ID: DB01097

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydroorotate dehydrogenase (DHODH) [2]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Mitochondrial ferroptosis regulatory signaling pathway; Regulation; N.A.
• In Vivo Model: Mouse model; Mus musculus
• Experiment for Molecule Alteration: Immunoprecipitation assay; LC-MS/MS analysis
• Experiment for Drug Resistance: Cellular ROS and lipid peroxidation level assay; LOXL3 enzymatic assay; In vitro kinase assay
• Mechanism Description: To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

ICD-15: Musculoskeletal/connective-tissue diseases

Rheumatoid arthritis [ICD-11: FA20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Mutation; p.P151S+p.R175H+p.G245C+p.R282W
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The wild-type p53 tumor suppressor (p53) is overexpressed in response to DNA damage and inflammation in RA fibroblast-like synoviocytes (FLS), which are highly specialized mesenchymal cells located in the internal lining of the synovium and are involved in the pathogenesis and progression of RA. In line with the effects of p53 gain-of-function mutation in tumor progression, mutation-mediated gain-of-function of p53 may contribute to the invasiveness and apoptosis-resistant feature of FLS in RA and the increased expression of cartilage degradative proteases, leading to degeneration of cartilage and bone. Gene knockout or gene transfer studies using a collagen-II-induced arthritis (CIA) model have established the crucial role of p53 in RA that provides a basis for additional research to fully characterize the clinical implications of p53 somatic mutations in drug-resistant RA.

References

• Ref 1: Drug-resistance in rheumatoid arthritis: the role of p53 gene mutations, ABC family transporters and personal factors .Curr Opin Pharmacol. 2020 Oct;54:59-71. doi: 10.1016/j.coph.2020.08.002. Epub 2020 Sep 14. 10.1016/j.coph.2020.08.002
• Ref 2: Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase. Nat Commun. 2023 May 30;14(1):3123.