Details of the Drug Combination

General Information of Drug Combination (ID: DCSVIGW)

• Drug Combination Name: Plicamycin + Valrubicin
• Indication: Cutaneous melanoma; Status: Investigative [1]
• Component Drugs:
  Plicamycin (DM7C8YV): Small molecular drug: 3D MOL is unavailable
  Valrubicin (DMOYJFK): Small molecular drug: 3D MOL is unavailable
• High-throughput Screening Result:
  Testing Cell Line: SK-MEL-28
  Zero Interaction Potency (ZIP) Score: 18.43
  Bliss Independence Score: 17.57
  Loewe Additivity Score: 15.5
  LHighest Single Agent (HSA) Score: 16.89

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Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[3]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 Valrubicin

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[5]
In situ carcinoma	N.A.	Approved	[6]
Urinary bladder cancer	N.A.	Approved	[6]
Psoriasis vulgaris	EA90	Phase 2	[2]

Valrubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Inhibitor	[15]

Valrubicin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCU67JC	HL-60(TB)	Investigative	[17]
Adult T acute lymphoblastic leukemia	DC1GRLT	MOLT-4	Investigative	[17]
Childhood T acute lymphoblastic leukemia	DCOS4XC	CCRF-CEM	Investigative	[17]
Chronic myelogenous leukemia	DC5ABT0	K-562	Investigative	[17]
Glioblastoma	DCNYQJF	SNB-75	Investigative	[17]
Glioma	DCBJ9PH	SF-539	Investigative	[17]
Glioma	DC3I9VJ	SF-268	Investigative	[17]
Plasma cell myeloma	DC5KT1B	RPMI-8226	Investigative	[17]
Invasive ductal carcinoma	DCQL7G7	BT-549	Investigative	[18]
Invasive ductal carcinoma	DC16DQ9	HS 578T	Investigative	[18]
Adenocarcinoma	DCR95X5	SW-620	Investigative	[1]
Adenocarcinoma	DCVQWJQ	HCT116	Investigative	[1]
Adenocarcinoma	DCCPQAN	HCT-15	Investigative	[1]
Amelanotic melanoma	DCA3LMJ	M14	Investigative	[1]
Cutaneous melanoma	DCBDBVE	SK-MEL-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCR5EDM	OVCAR-8	Investigative	[1]
Lung adenocarcinoma	DCV02ZH	HOP-62	Investigative	[1]
Lung adenocarcinoma	DC62ZF2	NCI-H522	Investigative	[1]
Malignant melanoma	DC5MYCQ	UACC62	Investigative	[1]
Malignant melanoma	DCKNM6V	LOX IMVI	Investigative	[1]
Melanoma	DC69ARK	MALME-3M	Investigative	[1]
Melanoma	DC2RBJA	SK-MEL-2	Investigative	[1]
Melanoma	DCSJVDW	UACC-257	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCKG4T6	NCI-H322M	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DCQ1BPG	IGROV1	Investigative	[1]
Ovarian serous cystadenocarcinoma	DC4O861	SK-OV-3	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] 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: 8394).
• [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] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [6] Valrubicin FDA Label
• [7] The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription. Chem Biol Interact. 2014 Aug 5;219:123-32. doi: 10.1016/j.cbi.2014.05.019. Epub 2014 Jun 4.
• [8] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [9] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [10] Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem. 2007 Jan 26;282(4):2615-25. doi: 10.1074/jbc.M606203200. Epub 2006 Nov 22.
• [11] Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6. doi: 10.1016/j.cbi.2009.09.018.
• [12] The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008 Jun;28(3):161-76. doi: 10.1042/BSR20080046.
• [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.
• [14] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [15] Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5.
• [16] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [17] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [18] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165