Drug Information

Drug (ID: DG01464) and It's Reported Resistant Information

• Name: Flutamide
• Synonyms: Flutamide; 13311-84-7; Eulexin; Niftolide; Niftholide; 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide; Sch 13521; NFBA; niftolid; Drogenil; Flutamin; Cebatrol, veterinary; Flutamida; Flutamidum; 4'-Nitro-3'-trifluoromethylisobutyranilide; Sch-13521; 2-Methyl-N-(4-nitro-3-[trifluoromethyl]phenyl)propanamide; N-(4-NITRO-3-(TRIFLUOROMETHYL)PHENYL)ISOBUTYRAMIDE; SCH13521; MFCD00072009; NSC 215876; Flutamide (Eulexin); alpha,alpha,alpha-Trifluoro-2-methyl-4'-nitro-m-propionotoluidide; UNII-76W6J0943E; CHEMBL806; Propanamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-; 4-Nitro-3-(trifluoromethyl)isobutyranilide; CHEBI:5132; Propanamide, 2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-; 76W6J0943E; NSC-215876; NCGC00015452-09; Eulexine; Chimax; 4'-Nitro-3'-trifluoromethylisobutyramilide; CAS-13311-84-7; Ham's F-12 medium; Flutamidum [INN-Latin]; DSSTox_CID_11121; DSSTox_RID_78899; DSSTox_GSID_32004; Flutamida [INN-Spanish]; Flutamide USP25; N-[4-Nitro-3-(trifluoromethyl)phenyl]isobutyramide; Prostandril; Odyne; SMR000058187; Eulexin (TN); CCRIS 7246; m-Propionotoluidide,.alpha.,.alpha.-trifluoro-; SR-01000075888; EINECS 236-341-9; BRN 2157663; .alpha.,.alpha.-Trifluoro-2-methyl-4'-nitro-m-propionotoluidide; m-Propionotoluidide,.alpha.,.alpha.-trifluoro-2-methyl-4'-nitro-; 4'-Nitro-3'-(trifluoromethyl)isobutyranilide; Flutamide [USAN:USP:INN:BAN]; Flutamide,(S); Prestwick_228; NK-601; Spectrum_001210; 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propionamide; CPD000058187; Prestwick0_000180; Prestwick1_000180; Prestwick2_000180; Prestwick3_000180; Spectrum2_001201; Spectrum3_001421; Spectrum4_000829; Spectrum5_001450; Lopac-F-9397; F0663; Flutamide (pubertal study); F 9397; SCHEMBL3934; Lopac0_000557; BSPBio_000079; BSPBio_003122; KBioGR_001377; KBioSS_001690; MLS000069634; MLS001065596; MLS002548892; DivK1c_000459; SPECTRUM1500995; SPBio_000982; SPBio_002000; Flutamide (JP17/USP/INN); BPBio1_000087; GTPL6943; CHEMBL4759307; DTXSID7032004; SCHEMBL12932289; HMS501G21; KBio1_000459; KBio2_001690; KBio2_004258; KBio2_006826; KBio3_002342; NINDS_000459; HMS1568D21; HMS1921O16; HMS2090I18; HMS2092O14; HMS2095D21; HMS2230P19; HMS3259I03; HMS3261P15; HMS3373C12; HMS3655G22; HMS3712D21; Pharmakon1600-01500995; AMY32524; BCP23006; HY-B0022; ZINC3812944; Tox21_110154; Tox21_202169; Tox21_300536; Tox21_500557; BDBM50131270; CCG-39105; m-Propionotoluidide, 2-methyl-4'-nitro-alpha,alpha,alpha-triflouro-; NSC147834; NSC215876; NSC757817; s1908; AKOS001025465; AKOS025243203; m-Propionotoluidide, .alpha.,.alpha.,.alpha.-trifluoro-2-methyl-4'-nitro-; Tox21_110154_1; AB02835; DB00499; KS-5091; LP00557; MCULE-7498839065; NC00451; NSC-147834; NSC-757817; SDCCGSBI-0050540.P004; IDI1_000459; NCGC00015452-01; NCGC00015452-02; NCGC00015452-03; NCGC00015452-04; NCGC00015452-05; NCGC00015452-06; NCGC00015452-07; NCGC00015452-08; NCGC00015452-10; NCGC00015452-11; NCGC00015452-12; NCGC00015452-13; NCGC00015452-14; NCGC00015452-15; NCGC00015452-16; NCGC00015452-19; NCGC00015452-20; NCGC00015452-32; NCGC00091460-01; NCGC00091460-02; NCGC00091460-03; NCGC00091460-04; NCGC00091460-05; NCGC00091460-06; NCGC00091460-07; NCGC00091460-08; NCGC00091460-09; NCGC00254495-01; NCGC00259718-01; NCGC00261242-01; AC-24192; BF166239; SY036411; SBI-0050540.P003; DB-042163; 3'-Trifluoromethyl-4'-Nitro-Isobutyranilide; AB00052188; EU-0100557; FT-0626493; FT-0668764; SW196536-4; 4''-nitro-3''-trifluoromethylisobutyranilide; C07653; D00586; J10037; AB00052188-09; AB00052188_10; AB00052188_11; 311F847; A806562; Q418669; Q-201131; SR-01000075888-1; SR-01000075888-6; SR-01000075888-7; SR-01000075888-9; BRD-K28307902-001-05-0; Flutamide, certified reference material, TraceCERT(R); Z56755651; a,a,a-Trifluoro-2-methyl-4'-nitro- m-propionotoluidide; Flutamide, European Pharmacopoeia (EP) Reference Standard; 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide #; Flutamide, United States Pharmacopeia (USP) Reference Standard; 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide;Flutamide; alpha,alpha,alpha-trifluoro-2-methyl-4''-nitro-m-propionotoluidide; .alpha.,.alpha.,.alpha.-Trifluoro-2-methyl-4'-nitro-m-propionotoluidide; m-Propionotoluidide, 2-methyl-4'-nitro-.alpha.,.alpha.,.alpha.-trifluoro-; m-Propionotoluidide, alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro- (8CI); Flutamide for system suitability, European Pharmacopoeia (EP) Reference Standard; 37209-54-4
• Indication:
  In total 4 Indication(s)
  Colorectal cancer [ICD-11: 2B91]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Tumour [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Prostate cancer [ICD-11: 2C82]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Prostate cancer [ICD-11: 2C82]; [2]
• Target: Candida Thymidylate synthase (Candi TMP1); TYSY_CANAL; [1]
• Target: Dihydrothymine dehydrogenase (DPYD); DPYD_HUMAN; [1]
• Target: TERT messenger RNA (TERT mRNA); TERT_HUMAN; [1]
• Target: Thymidylate synthase messenger RNA (TYMS mRNA); TYSY_HUMAN; [1]
• Formula: 2
• IsoSMILES: CC(C)C(=O)NC1=CC(=C(C=C1)[N+](=O)[O-])C(F)(F)F
• InChI: InChI=1S/C11H11F3N2O3/c1-6(2)10(17)15-7-3-4-9(16(18)19)8(5-7)11(12,13)14/h3-6H,1-2H3,(H,15,17)
• InChIKey: MKXKFYHWDHIYRV-UHFFFAOYSA-N
• PubChem CID: 3397
• ChEBI ID: CHEBI:5132
• TTD Drug ID: D05LEO
• VARIDT ID: DR0733
• INTEDE ID: DR00846
• DrugBank ID: DB00499

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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

Prostate cancer [ICD-11: 2C82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Androgen receptor (AR) [1]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Missense mutation; p.T878A (c.2632A>G)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.44 Å; PDB: 5V8Q
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.20 Å; PDB: 8E1A

RMSD: 0.92; TM score: 0.98421; Amino acid change: T878A

• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Androgen receptor (AR) [1]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Missense mutation; p.T877A
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Androgen receptor (AR) [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN-FLU cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: To obtain molecular evidence of the acquired resistance of the LN-FLU cells, we checked the expressions of significant proteins involved in prostate cell growth. As shown in, the LN-FLU cells showed less expression of the androgen receptor (AR) compared with the parental LNCaP cells, further confirming the androgen refractory state of the cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: P-glycoprotein 1A (ABCB1A) [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN-FLU cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1A, a well-known multidrug-resistant protein that expels drugs outside the cell, thereby promoting drug resistance, was increased in the LN-FLU cells

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: LN-FLU cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The PI3K/Akt/mTOR pathway is involved in the regulation of cancer cell survival, proliferation, growth, and metabolism. In most prostate cancer cell lines, the PIP3 phosphatase PTEN, which antagonizes this pathway, is mutated and therefore the PI3K/Akt/mTOR pathway is activated. To examine the functioning of this pathway, we determined the expressions and phosphorylation levels of Akt and mTOR via Western blot. As shown in, in the drug-resistant LN-FLU cells, both the phosphorylation levels and overall expressions of Akt and mTOR were decreased when compared to the LNCaP cells. The results in the LN-FLU cells were similar to those observed in the androgen-resistant PC3 cells, which were used as a positive control. The decrease in Akt and mTOR signaling suggests a proliferative arrest of the drug-resistant LN-FLU cells.

Key Molecule: AKT serine/threonine kinase (AKT) [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: LN-FLU cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The PI3K/Akt/mTOR pathway is involved in the regulation of cancer cell survival, proliferation, growth, and metabolism. In most prostate cancer cell lines, the PIP3 phosphatase PTEN, which antagonizes this pathway, is mutated and therefore the PI3K/Akt/mTOR pathway is activated. To examine the functioning of this pathway, we determined the expressions and phosphorylation levels of Akt and mTOR via Western blot. As shown in, in the drug-resistant LN-FLU cells, both the phosphorylation levels and overall expressions of Akt and mTOR were decreased when compared to the LNCaP cells. The results in the LN-FLU cells were similar to those observed in the androgen-resistant PC3 cells, which were used as a positive control. The decrease in Akt and mTOR signaling suggests a proliferative arrest of the drug-resistant LN-FLU cells.

References

• Ref 1: A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgensBiochem Biophys Res Commun. 1990 Dec 14;173(2):534-40. doi: 10.1016/s0006-291x(05)80067-1.
• Ref 2: Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications. Int J Mol Sci. 2023 Oct 26;24(21):15626.