Details of the Drug Combination

General Information of Drug Combination (ID: DCIB3Z3)

• Drug Combination Name: Plicamycin + Busulfan
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Plicamycin (DM7C8YV): Small molecular drug
  Busulfan (DMXYJ9C): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CAKI-1
  Zero Interaction Potency (ZIP) Score: 8.59
  Bliss Independence Score: 15.59
  Loewe Additivity Score: 4.42
  LHighest Single Agent (HSA) Score: 3.29

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[2]
Testicular cancer	2C80	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[3]
Lung cancer	2C25.0	Investigative	[4]
Ovarian cancer	2C73	Investigative	[4]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[8]

Plicamycin Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[9]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[10]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[11]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[12]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[7]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[11]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[13]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[14]

Indication(s) of Busulfan

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[5]
Hematologic disease	3C0Z	Approved	[5]
Immunodeficiency	4A00-4A85	Approved	[5]
Leukemia	N.A.	Approved	[5]
Myeloproliferative syndrome	2A22	Approved	[6]
Systemic lupus erythematosus	4A40.0	Approved	[5]
Systemic sclerosis	4A42	Approved	[5]
Neuroblastoma	2D11.2	Investigative	[5]
Retinoblastoma	2D02.2	Investigative	[5]

Busulfan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[16]

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	[17]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[18]
Glutathione S-transferase alpha-2 (GSTA2)	DEH49YS	GSTA2_HUMAN	Metabolism	[19]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[20]
Microsomal glutathione S-transferase 2 (MGST2)	DE31KMQ	MGST2_HUMAN	Metabolism	[21]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[20]

Busulfan Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serotransferrin (TF)	OT41PEMS	TRFE_HUMAN	Increases Expression	[22]
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Affects Expression	[23]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[24]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[24]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[25]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[25]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[15]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Activity	[26]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Activity	[26]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[26]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Decreases Expression	[15]
Pseudouridylate synthase 7 homolog (PUS7)	OTE5AQHJ	PUS7_HUMAN	Increases Expression	[27]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[28]
Rho GDP-dissociation inhibitor 1 (ARHGDIA)	OTEXWJDO	GDIR1_HUMAN	Affects Response To Substance	[29]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Chronic myelogenous leukemia	DCFFY0F	K-562	Investigative	[1]
Glioma	DCXVJIA	SF-539	Investigative	[1]
Renal cell carcinoma	DCUX9QA	UO-31	Investigative	[1]
Invasive ductal carcinoma	DCLEK33	T-47D	Investigative	[30]
Mixed endometrioid and clear cell carcinoma	DC6NUZ8	IGROV1	Investigative	[31]

References

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• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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• [4] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
• [5] Busulfan FDA Label
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• [13] Sp sites contribute to basal and inducible expression of the human TNIP1 (TNF-inducible protein 3-interacting protein 1) promoter. Biochem J. 2013 Jun 15;452(3):519-29. doi: 10.1042/BJ20121666.
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• [20] Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9.
• [21] Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25.
• [22] 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.
• [23] 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.
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