General Information of Drug Combination (ID: DCEB2W6)

Drug Combination Name
Indazole derivative 5 Chlorambucil
Indication
Disease Entry Status REF
Adult T acute lymphoblastic leukemia Investigative [1]
Component Drugs Indazole derivative 5   DMM1I8R Chlorambucil   DMRKE63
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: MOLT-4
Zero Interaction Potency (ZIP) Score: 4.71
Bliss Independence Score: 7.04
Loewe Additivity Score: 5.2
LHighest Single Agent (HSA) Score: 7.38

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indazole derivative 5 Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
ABL T315I mutant (ABL T315I) TTZJTWA ABL1_HUMAN Inhibitor [4]
Fusion protein Bcr-Abl T315I mutant (Bcr-Abl T315I) TTIV39N BCR_HUMAN-ABL1_HUMAN Inhibitor [4]
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Indication(s) of Chlorambucil
Disease Entry ICD 11 Status REF
Chronic lymphocytic leukaemia 2A82.0 Approved [2]
Small lymphocytic lymphoma 2A82.0 Approved [3]
Classic Hodgkin lymphoma N.A. Investigative [3]
Follicular lymphoma 2A80 Investigative [3]
Chlorambucil Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
DNA replication (DNA repli) TTABD5E NOUNIPROTAC Intercalator [5]
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Chlorambucil Interacts with 2 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [6]
Organic anion transporting polypeptide 1A2 (SLCO1A2) DTE2B1D SO1A2_HUMAN Substrate [7]
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Chlorambucil Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Glutathione S-transferase pi (GSTP1) DEK6079 GSTP1_HUMAN Metabolism [8]
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Chlorambucil Interacts with 37 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Glutathione S-transferase P (GSTP1) OTLP0A0Y GSTP1_HUMAN Decreases Response To Substance [9]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [10]
Glutathione S-transferase A1 (GSTA1) OTA7K5XA GSTA1_HUMAN Decreases Activity [11]
Aldo-keto reductase family 1 member B10 (AKR1B10) OTOA4HTH AK1BA_HUMAN Decreases Expression [12]
Leukemia inhibitory factor (LIF) OTO46S5S LIF_HUMAN Increases Expression [12]
Aldo-keto reductase family 1 member C2 (AKR1C2) OTQ2XMO3 AK1C2_HUMAN Decreases Expression [12]
Bcl-2-interacting killer (BIK) OTTH1T3D BIK_HUMAN Increases Expression [12]
F-box only protein 30 (FBXO30) OTD1P6LA FBX30_HUMAN Decreases Expression [12]
Histone chaperone ASF1A (ASF1A) OT4S44GP ASF1A_HUMAN Decreases Expression [12]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A) OTBPCU2O TR10A_HUMAN Affects Expression [13]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) OTA1CPBV TR10B_HUMAN Increases Expression [14]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Affects Expression [15]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Increases Expression [16]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [14]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [16]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Phosphorylation [17]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1) OT7OG7Y2 DPA1_HUMAN Affects Expression [18]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Increases Expression [19]
14-3-3 protein sigma (SFN) OTLJCZ1U 1433S_HUMAN Increases Expression [14]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [20]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [19]
Histone H4 (H4C1) OTB71W46 H4_HUMAN Decreases Expression [17]
E3 ubiquitin-protein ligase Mdm2 (MDM2) OTOVXARF MDM2_HUMAN Increases Expression [15]
DNA repair protein RAD51 homolog 1 (RAD51) OTNVWGC1 RAD51_HUMAN Increases Expression [21]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [22]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Activity [19]
kinase isozyme 4, mitochondrial (PDK4) OTCMHMBZ PDK4_HUMAN Affects Expression [23]
Bcl-2-binding component 3, isoforms 3/4 (BBC3) OTUAXDAY BBC3B_HUMAN Increases Expression [15]
Nuclear factor erythroid 2-related factor 2 (NFE2L2) OT0HENJ5 NF2L2_HUMAN Increases Response To Substance [24]
Dihydrofolate reductase (DHFR) OT3DVIGM DYR_HUMAN Decreases Response To Substance [25]
Cytidine deaminase (CDA) OT3HXP6N CDD_HUMAN Decreases Response To Substance [26]
Fanconi anemia group G protein (FANCG) OT7MC8TZ FANCG_HUMAN Increases Response To Substance [27]
Baculoviral IAP repeat-containing protein 2 (BIRC2) OTFXFREP BIRC2_HUMAN Decreases Response To Substance [28]
Multidrug resistance-associated protein 1 (ABCC1) OTGUN89S MRP1_HUMAN Decreases Response To Substance [9]
ATP-binding cassette sub-family C member 2 (ABCC2) OTJSIGV5 MRP2_HUMAN Affects Export [29]
Glutathione S-transferase Mu 1 (GSTM1) OTSBF2MO GSTM1_HUMAN Decreases Response To Substance [30]
Fanconi anemia group C protein (FANCC) OTTIDM3P FANCC_HUMAN Increases Response To Substance [27]
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⏷ Show the Full List of 37 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Plasma cell myeloma DC61HV7 RPMI-8226 Investigative [1]
Melanoma DC3RID1 SK-MEL-2 Investigative [31]
Non-small cell lung carcinoma DC2W54V HOP-92 Investigative [31]
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References

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2 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7143).
3 Chlorambucil FDA Label
4 Bcr-Abl tyrosine kinase inhibitors: a patent review.Expert Opin Ther Pat. 2015 Apr;25(4):397-412.
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8 The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants. J Mol Biol. 2008 Jun 27;380(1):131-44.
9 The influence of coordinate overexpression of glutathione phase II detoxification gene products on drug resistance. J Pharmacol Exp Ther. 2000 Aug;294(2):480-7.
10 Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs. Int J Cancer. 2004 Sep 10;111(4):484-93. doi: 10.1002/ijc.20230.
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12 Oxidative stress mechanisms do not discriminate between genotoxic and nongenotoxic liver carcinogens. Chem Res Toxicol. 2015 Aug 17;28(8):1636-46.
13 Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene. 2003 Nov 13;22(51):8356-69. doi: 10.1038/sj.onc.1207004.
14 Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. J Cell Biochem. 2008 May 15;104(2):595-605. doi: 10.1002/jcb.21649.
15 Differential gene expression induction by TRAIL in B chronic lymphocytic leukemia (B-CLL) cells showing high versus low levels of Zap-70. J Cell Physiol. 2007 Oct;213(1):229-36. doi: 10.1002/jcp.21116.
16 Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells. Blood. 1996 Sep 15;88(6):2172-82.
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19 Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation. Blood. 2001 Nov 1;98(9):2800-7. doi: 10.1182/blood.v98.9.2800.
20 Disruption of gene expression and induction of apoptosis in prostate cancer cells by a DNA-damaging agent tethered to an androgen receptor ligand. Chem Biol. 2005 Jul;12(7):779-87. doi: 10.1016/j.chembiol.2005.05.009.
21 Chlorambucil induction of HsRad51 in B-cell chronic lymphocytic leukemia. Clin Cancer Res. 1999 Aug;5(8):2178-84.
22 Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk Lymphoma. 2001 Jul;42(3):491-8. doi: 10.3109/10428190109064606.
23 The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
24 Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis. 2009 Sep;30(9):1571-80. doi: 10.1093/carcin/bgp176. Epub 2009 Jul 16.
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30 Glutathione S-transferase M1 and multidrug resistance protein 1 act in synergy to protect melanoma cells from vincristine effects. Mol Pharmacol. 2004 Apr;65(4):897-905. doi: 10.1124/mol.65.4.897.
31 Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.