Drug Information

Drug (ID: DG01800) and It's Reported Resistant Information

• Name: Simvastatin
• Synonyms: Simvastatin; 79902-63-9; Zocor; Synvinolin; Sinvacor; Denan; Lipex; MK-733; Sivastin; Lodales; Simvastatine; Cholestat; Colemin; Simovil; Medipo; Pantok; Simvastatina; Simvastatinum; Velostatin; Zocord; Zorced; Simvastatin lactone; Simvastatin (Zocor); Lipovas; Simcard; Simvacor; Simvoget; Rechol; Simlup; (1S,3R,7S,8S,8aR)-8-(2-((2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate; MK-0733; UNII-AGG2FN16EV; MK 733; 2,2-Dimethylbutyric acid, 8-ester with (4R,6R)-6-(2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl)ethyl)tetrahydro-4-hydroxy-2H-pyran-2-one; AGG2FN16EV; CHEBI:9150; (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate; [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate; Labistatin; Coledis; Corolin; Nivelipol; Rendapid; Vasotenal; NSC-758706; Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester; C25H38O5; Simvastatine [French]; Simvastatinum [Latin]; Simvastatina [Spanish]; DSSTox_CID_3581; DSSTox_RID_77090; DSSTox_GSID_23581; Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-((2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester; Zosta; Simvast CR; DRG-0320; [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate; SMR000718785; MK 0733; CCRIS 7558; Zocor (TN); HSDB 7208; Simvastatin & Primycin; MK733; SR-05000001894; (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate; L 644128-000U; BRN 4768037; Kolestevan; Lipinorm; Modutrol; Simvotin; Sinvascor; Valemia; Eucor; MFCD00072007; Nor-Vastina; Simvastatin,(S); C10AA01; simvastatin predrug; (+)-Simvastatin; NCGC00016940-01; inactive simvastatin; Simvastatin [USAN:USP:INN:BAN]; TNP00259; Prestwick_171; Simvastatin- Bio-X; CAS-79902-63-9; KS-1113; Spectrum_001717; SpecPlus_000895; Prestwick0_000865; Prestwick1_000865; Prestwick2_000865; Prestwick3_000865; Spectrum2_001671; Spectrum3_000669; Spectrum4_000632; Spectrum5_001428; SCHEMBL2471; CHEMBL1064; BSPBio_000909; BSPBio_002337; KBioGR_001244; KBioSS_002197; MLS001304029; MLS001333077; MLS001333078; MLS002154038; MLS006011866; BIDD:GT0769; DivK1c_006991; SPECTRUM1504236; SPBio_001881; SPBio_002830; BPBio1_001001; GTPL2955; Simvastatin (JP17/USP/INN); Simvastatin, analytical standard; DTXSID0023581; BCBcMAP01_000007; KBio1_001935; KBio2_002197; KBio2_004765; KBio2_007333; KBio3_001557; RYMZZMVNJRMUDD-HGQWONQESA-; HMS1570N11; HMS1922H13; HMS2089D12; HMS2093E06; HMS2097N11; HMS2231N22; HMS3259B12; HMS3412P08; HMS3676P08; HMS3714N11; HMS3884G10; Pharmakon1600-01504236; ZINC3780893; Tox21_110696; Tox21_300400; BBL024390; BDBM50139181; CCG-39069; NSC633782; NSC758706; s1792; STK801938; AKOS005111006; AKOS015842733; Simvastatin, >=97% (HPLC), solid; Tox21_110696_1; AC-1530; DB00641; MCULE-8390617062; NC00719; NSC 758706; NSC-633782; MRF-0000729; NCGC00017324-01; NCGC00017324-02; NCGC00017324-03; NCGC00017324-04; NCGC00017324-05; NCGC00017324-07; NCGC00017324-08; NCGC00017324-09; NCGC00254418-01; 2,2-Dimethylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester; BS164407; Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1alpha,3alpha,7beta,8beta(2S*,4S*),8abeta))-; HY-17502; SBI-0206773.P001; Simvastatin 100 microg/mL in Acetonitrile; S0509; D00434; J10128; AB00053395-07; AB00053395-08; AB00053395-10; AB00053395_11; AB00053395_13; 902S639; A839783; Q670131; SR-05000001894-1; SR-05000001894-2; BRD-K22134346-001-05-8; BRD-K22134346-001-11-6; BRD-K22134346-001-15-7; Z1741982918; Simvastatin, British Pharmacopoeia (BP) Reference Standard; Simvastatin, European Pharmacopoeia (EP) Reference Standard; Simvastatin, United States Pharmacopeia (USP) Reference Standard; Simvastatin, Pharmaceutical Secondary Standard; Certified Reference Material; Simvastatin for peak identification, European Pharmacopoeia (EP) Reference Standard; (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyly-2,2-dimethyl butanoate; (1S,3R,7S,8S,8aR)-8-(2-((2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbu; (1S,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate
• Indication:
  In total 1 Indication(s)
  Hypercholesterolaemia [ICD-11: 5C80]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Alzheimer's disease [ICD-11: 8A20]; [1]
  Brain cancer [ICD-11: 2A00]; [2]
• Target: HMG-CoA reductase (HMGCR); HMDH_HUMAN; [1]
• Formula: 7
• IsoSMILES: CCC(C)(C)C(=O)O[C@H]1C[C@H](C=C2[C@H]1[C@H]([C@H](C=C2)C)CC[C@@H]3C[C@H](CC(=O)O3)O)C
• InChI: InChI=1S/C25H38O5/c1-6-25(4,5)24(28)30-21-12-15(2)11-17-8-7-16(3)20(23(17)21)10-9-19-13-18(26)14-22(27)29-19/h7-8,11,15-16,18-21,23,26H,6,9-10,12-14H2,1-5H3/t15-,16-,18+,19+,20-,21-,23-/m0/s1
• InChIKey: RYMZZMVNJRMUDD-HGQWONQESA-N
• PubChem CID: 54454
• ChEBI ID: CHEBI:9150
• TTD Drug ID: D0H0ND
• VARIDT ID: DR1485
• INTEDE ID: DR00435
• DrugBank ID: DB00641

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Forkhead box M1 (FOXM1) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Terpenoid backbone biosynthesis; Activation; hsa00900
• In Vivo Model: NOD/SCID mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Like dipyridamole (41, 57), caffeine can block statin-induced feedback activation of SREBP2 and mevalonate pathway enzymes. Our data suggest that this action of caffeine depends on its activity as an antagonist of adenosine receptors (43, 59, 62), as evidenced by the findings that supplemental adenosine can abrogate the ability of caffeine to block statin-induced feedback activation SREBP2 and mevalonate pathway enzymes and to enhance the antigrowth effect of simvastatin.

Key Molecule: Sterol regulatory element binding protein 2 (SREBP2) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Terpenoid backbone biosynthesis; Activation; hsa00900
• In Vivo Model: NOD/SCID mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our data are consistent with a recent study in liver cancer cell lines showing that statin represses FOXM1 expression by blocking geranylgeranylation of RhoA, Rac1 or Cdc42 proteins (46). Together, these findings suggest a molecular mechanism for the long-observed connection between the mevalonate pathway and cell-cycle progression (47).

Multiple myeloma [ICD-11: 2A83]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Ubiquinone (Q10) [3]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AMO-1 cells; Blood; Homo sapiens (Human); CVCL_1806
• In Vitro Model: ARH-77 cells; Peripheral blood; Homo sapiens (Human); CVCL_1072
• In Vitro Model: MM RPMI-8226 cells; Blood; Homo sapiens (Human); CVCL_0014
• Experiment for Molecule Alteration: Proteomics
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.

ICD-08: Nervous system diseases

Alzheimer's disease [ICD-11: 8A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (N336694) [1]

• Resistant Disease: Alzheimer's disease [ICD-11: 8A20.0]
• Molecule Alteration: Up-regulation; Expression/Mutation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• Experiment for Molecule Alteration: ELISA assay; Western bloting analysis; qRT-PCR
• Mechanism Description: Alzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits.

References

• Ref 1: Simvastatin ameliorate memory deficits and inflammation in clinical and mouse model of Alzheimer's disease via modulating the expression of miR-106bBiomed Pharmacother. 2017 Aug;92:46-57. doi: 10.1016/j.biopha.2017.05.060. Epub 2017 May 18.
• Ref 2: Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma. Cancer Res. 2023 Jul 5;83(13):2248-2261.
• Ref 3: Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma. Mol Omics. 2022 Jan 17;18(1):19-30.