Details of the Drug Combination

General Information of Drug Combination (ID: DCE3PJK)

• Drug Combination Name: Nilotinib + Busulfan
• Indication: Glioma; Status: Investigative [1]
• Component Drugs:
  Nilotinib (DM7HXWT): Small molecular drug
  Busulfan (DMXYJ9C): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SF-539
  Zero Interaction Potency (ZIP) Score: 0.63
  Bliss Independence Score: 3.55
  Loewe Additivity Score: 1.53
  LHighest Single Agent (HSA) Score: 1.54

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Nilotinib

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[2]

Nilotinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Fusion protein Bcr-Abl (Bcr-Abl)	TTS7G69	BCR_HUMAN-ABL1_HUMAN	Modulator	[8]

Nilotinib Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[9]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[11]

Nilotinib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]

Nilotinib Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Response To Substance	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Response To Substance	[15]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[16]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[7]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[7]
Homeobox protein Hox-B7 (HOXB7)	OTC7WYU8	HXB7_HUMAN	Increases Expression	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[7]
Homeobox protein Hox-B9 (HOXB9)	OTMVHQOU	HXB9_HUMAN	Increases Expression	[6]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Decreases Expression	[7]
Paired box protein Pax-3 (PAX3)	OTN5PJZV	PAX3_HUMAN	Decreases Expression	[6]
Paired box protein Pax-6 (PAX6)	OTOC9876	PAX6_HUMAN	Increases Expression	[6]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[7]
Crk-like protein (CRKL)	OTOYSD1R	CRKL_HUMAN	Decreases Phosphorylation	[7]
Homeobox protein MOX-1 (MEOX1)	OTJEMT2D	MEOX1_HUMAN	Decreases Expression	[6]
Mesoderm posterior protein 2 (MESP2)	OT7H4LYA	MESP2_HUMAN	Decreases Expression	[6]
Transcription factor 15 (TCF15)	OTA6UCWC	TCF15_HUMAN	Decreases Expression	[6]
Oligodendrocyte transcription factor 3 (OLIG3)	OTU8XLAF	OLIG3_HUMAN	Increases Expression	[6]
ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1)	OTWHN69S	EDEM1_HUMAN	Increases Expression	[7]
Eyes absent homolog 1 (EYA1)	OTHU807A	EYA1_HUMAN	Decreases Expression	[6]
Neurogenin-2 (NEUROG2)	OTAEMIGT	NGN2_HUMAN	Increases Expression	[6]

Indication(s) of Busulfan

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[3]
Hematologic disease	3C0Z	Approved	[3]
Immunodeficiency	4A00-4A85	Approved	[3]
Leukemia	N.A.	Approved	[3]
Myeloproliferative syndrome	2A22	Approved	[4]
Systemic lupus erythematosus	4A40.0	Approved	[3]
Systemic sclerosis	4A42	Approved	[3]
Neuroblastoma	2D11.2	Investigative	[3]
Retinoblastoma	2D02.2	Investigative	[3]

Busulfan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[19]

Busulfan Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[21]
Glutathione S-transferase alpha-2 (GSTA2)	DEH49YS	GSTA2_HUMAN	Metabolism	[22]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[23]
Microsomal glutathione S-transferase 2 (MGST2)	DE31KMQ	MGST2_HUMAN	Metabolism	[24]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[23]

Busulfan Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serotransferrin (TF)	OT41PEMS	TRFE_HUMAN	Increases Expression	[25]
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Affects Expression	[26]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[27]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[27]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[28]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[28]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[18]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[18]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Activity	[29]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Activity	[29]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[29]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Decreases Expression	[18]
Pseudouridylate synthase 7 homolog (PUS7)	OTE5AQHJ	PUS7_HUMAN	Increases Expression	[30]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[31]
Rho GDP-dissociation inhibitor 1 (ARHGDIA)	OTEXWJDO	GDIR1_HUMAN	Affects Response To Substance	[32]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Astrocytoma	DCGB4BB	SNB-19	Investigative	[1]
Adenocarcinoma	DC0KFHQ	DU-145	Investigative	[33]
Adenocarcinoma	DCCURTI	NCIH23	Investigative	[33]
Adenocarcinoma	DCX423W	HCT116	Investigative	[33]
Amelanotic melanoma	DCLO7M2	M14	Investigative	[33]
Cutaneous melanoma	DC7VEX6	SK-MEL-28	Investigative	[33]
Malignant melanoma	DCNWSHD	LOX IMVI	Investigative	[33]
Prostate carcinoma	DCRTSJ3	PC-3	Investigative	[33]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [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: 5697).
• [3] Busulfan FDA Label
• [4] 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: 7136).
• [5] Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol. 2016 Apr;90:112-22.
• [6] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [7] Endoplasmic reticulum stress-mediated apoptosis in imatinib-resistant leukemic K562-r cells triggered by AMN107 combined with arsenic trioxide. Exp Biol Med (Maywood). 2013 Aug 1;238(8):932-42. doi: 10.1177/1535370213492689. Epub 2013 Jul 24.
• [8] 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
• [9] Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol. 2009 Oct;158(4):1153-64.
• [10] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01665)
• [11] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [12] Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87.
• [13] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [14] Resistance to daunorubicin, imatinib, or nilotinib depends on expression levels of ABCB1 and ABCG2 in human leukemia cells. Chem Biol Interact. 2014 Aug 5;219:203-10. doi: 10.1016/j.cbi.2014.06.009. Epub 2014 Jun 19.
• [15] Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels. Chem Biol Interact. 2017 Aug 1;273:171-179. doi: 10.1016/j.cbi.2017.06.012. Epub 2017 Jun 13.
• [16] Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
• [17] Nilotinib reduced the viability of human ovarian cancer cells via mitochondria-dependent apoptosis, independent of JNK activation. Toxicol In Vitro. 2016 Mar;31:1-11. doi: 10.1016/j.tiv.2015.11.002. Epub 2015 Nov 6.
• [18] Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air-liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells. Cell Biol Toxicol. 2023 Feb;39(1):1-18. doi: 10.1007/s10565-022-09726-0. Epub 2022 May 31.
• [19] DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. Cancer Sci. 2004 May;95(5):454-8.
• [20] Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998 Jan-Feb;18(1):84-112.
• [21] Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004 Sep 1;104(5):1574-7.
• [22] Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation. Eur J Haematol. 2008 Apr;80(4):299-302.
• [23] Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9.
• [24] Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25.
• [25] Busulfan induces activin A expression in vitro and in vivo: a possible link to venous occlusive disease. Clin Pharmacol Ther. 2003 Sep;74(3):264-74.
• [26] Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005 May;84(5):321-30. doi: 10.1007/s00277-004-0982-4. Epub 2004 Dec 4.
• [27] Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis. Eur J Clin Pharmacol. 2012 Jun;68(6):923-35. doi: 10.1007/s00228-011-1209-y.
• [28] Altered gene expression in busulfan-resistant human myeloid leukemia. Leuk Res. 2008 Nov;32(11):1684-97. doi: 10.1016/j.leukres.2008.01.016. Epub 2008 Mar 12.
• [29] Busulfan selectively induces cellular senescence but not apoptosis in WI38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. J Pharmacol Exp Ther. 2006 Nov;319(2):551-60. doi: 10.1124/jpet.106.107771. Epub 2006 Aug 1.
• [30] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [31] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [32] Reduced expression of Rho guanine nucleotide dissociation inhibitor-alpha modulates the cytotoxic effect of busulfan in HEK293 cells. Anticancer Drugs. 2007 Mar;18(3):333-40. doi: 10.1097/CAD.0b013e328011fd7f.
• [33] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976