Drug Information

Drug (ID: DG01471) and It's Reported Resistant Information

• Name: Idarubicin
• Synonyms: IDARUBICIN; 58957-92-9; 4-Demethoxydaunorubicin; 4-Demethoxydaunomycin; Idarubicine [INN-French]; Idarubicinum [INN-Latin]; Idarubicina [INN-Spanish]; UNII-ZRP63D75JW; NSC 256439; NSC-256439; ZRP63D75JW; (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione; Idarubicina; CHEBI:42068; (1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside; 5,12-Naphthacenedione, 9-acetyl-7-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,9,11-trihydroxy-, (7S-cis)-; Idarubicine; Idarubicinum; Idarubicin [INN:BAN]; Idarubicinhydrochloride; DM5; MLS001401448; Daunomycin, 4-demethoxy-; NSC256439; (1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside; (7S,9S)-9-acetyl-7-{[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione; Idarubicin (INN); Zavedos (TN); CCRIS 5083; NCGC00093976-03; SMR000466355; 4-DMD; SR-01000075934; I 1656; SCHEMBL3750; CHEMBL1117; Lopac0_000600; KBioSS_002388; Idarubicin hydrochloride, solid; cid_636362; GTPL7083; 4-DEMETHOXY-DAUNORUBICIN; DTXSID7023142; IDARUBICIN(Hydrochloride form); BDBM58490; BCPP000207; HMS2089D05; HMS3261H22; (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride; ZINC3920266; Tox21_500600; AKOS015895563; AC-9384; BCP9000773; CCG-204689; DB01177; LP00600; SDCCGSBI-0050582.P002; NCGC00093976-01; NCGC00093976-02; NCGC00093976-04; NCGC00093976-05; NCGC00093976-18; NCGC00261285-01; (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione; 5,12-Naphthacenedione, 7,8,9,10-tetrahydro-9-acetyl-7-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-6,9,11-trihydroxy-, (7S-cis)-; EU-0100600; D08062; AB00698511-06; AB00698511-08; AB00698511-09; AB00698511-10; AB00698511_11; 957I929; A832088; A935911; Q1063862; SR-01000075934-1; BRD-K69650333-001-01-1; BRD-K69650333-001-02-9; BRD-K69650333-003-14-0; Idarubicin, United States Pharmacopeia (USP) Reference Standard; (7S,9S)-7-[(2R,4S,5S,6S)-4-azanyl-6-methyl-5-oxidanyl-oxan-2-yl]oxy-9-ethanoyl-6,9,11-tris(oxidanyl)-8,10-dihydro-7H-tetracene-5,12-dione; (7S,9S)-7-[(2R,4S,5S,6S)-4-azanyl-6-methyl-5-oxidanyl-oxan-2-yl]oxy-9-ethanoyl-6,9,11-tris(oxidanyl)-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride; (7S,9S)-9-Acetyl-7-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,9,11-trihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione; (7S,9S)-9-acetyl-7-((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)-6,9,11-trihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione; (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-quinone;hydrochloride; (7S,9S)-9-acetyl-7-[[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-2-oxanyl]oxy]-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione; (7S,9S)-9-acetyl-7-[[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-2-oxanyl]oxy]-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride; 4-Demethoxydaunorubicin; ; ; IMI-30; ; ; NSC-256439; ; ; (7S,9S)-9-Acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione; 5,12-Naphthacenedione, 7,8,9,10-tetrahydro-9-acetyl-7-((3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranosyl)oxy)-6,9,11-trihydroxy-, (7S-cis)-
• Indication:
  In total 1 Indication(s)
  Heart arrhythmia [ICD-11: BC65]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [2]
• Formula: 3
• IsoSMILES: C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C2C(=C4C(=C3O)C(=O)C5=CC=CC=C5C4=O)O)(C(=O)C)O)N)O
• InChI: InChI=1S/C26H27NO9/c1-10-21(29)15(27)7-17(35-10)36-16-9-26(34,11(2)28)8-14-18(16)25(33)20-19(24(14)32)22(30)12-5-3-4-6-13(12)23(20)31/h3-6,10,15-17,21,29,32-34H,7-9,27H2,1-2H3/t10-,15-,16-,17-,21+,26-/m0/s1
• InChIKey: XDXDZDZNSLXDNA-TZNDIEGXSA-N
• PubChem CID: 42890
• ChEBI ID: CHEBI:42068
• TTD Drug ID: D0Y9LL
• VARIDT ID: DR0852
• INTEDE ID: DR00386
• DrugBank ID: DB01177

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

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [3]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCG2 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Induction of DNA double-strand breaks and chromatin damage through histone eviction;Less affected by ABCG2-mediated drug export.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-glycoprotein; Regulation; N.A.
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562 ABCB1 overexpression cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Flow Cytometry assay; DNA dye competition assay
• Mechanism Description: Induction of DNA double-strand breaks and chromatin damage through histone eviction.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNA Damage Response Mechanism; Regulation; N.A.
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
• Mechanism Description: DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.

Key Molecule: Acetyl-CoA acetyltransferase 2 (ACAT2) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNA Damage Response Mechanism; Regulation; N.A.
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
• Mechanism Description: DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients.

Key Molecule: Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNA Damage Response Mechanism; Regulation; N.A.
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: TF-1 cells; Blood; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
• Mechanism Description: DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.R882H (c.2645G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.40 Å; PDB: 6W8B
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.44 Å; PDB: 6W8J

RMSD: 0.46; TM score: 0.99493; Amino acid change: R882H

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• In Vivo Model: NOD/SCID mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.R882H (c.2645G>A) in gene DNMT3A cause the sensitivity of Idarubicin by unusual activation of pro-survival pathway

References

• Ref 1: Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin A single center experienceOncotarget. 2011 Nov;2(11):850-61. doi: 10.18632/oncotarget.347.
• Ref 2: Silencing of the DNA damage repair regulator PPP1R15A sensitizes acute myeloid leukemia cells to chemotherapy. Ann Hematol. 2024 Aug;103(8):2853-2863.
• Ref 3: Novel N,N-Dimethyl-idarubicin Analogues Are Effective Cytotoxic Agents for ABCB1-Overexpressing, Doxorubicin-Resistant Cells. J Med Chem. 2024 Aug 22;67(16):13802-13812.