Details of the Drug Combination

General Information of Drug Combination (ID: DC1ABVZ)

• Drug Combination Name: Raloxifene + Plicamycin
• Indication: High grade ovarian serous adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Raloxifene (DMDKF3M): Small molecular drug
  Plicamycin (DM7C8YV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: OVCAR-8
  Zero Interaction Potency (ZIP) Score: 2.17
  Bliss Independence Score: 9.02
  Loewe Additivity Score: 3.77
  LHighest Single Agent (HSA) Score: 3.83

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Raloxifene

Disease Entry	ICD 11	Status	REF
Osteoporosis	FB83.0	Approved	[2]

Raloxifene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Modulator	[5]

Raloxifene Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Raloxifene Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[9]

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Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[3]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	[11]

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	[12]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[13]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[14]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[15]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[10]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[14]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[16]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCUUWEB	HL-60(TB)	Investigative	[18]
Adult T acute lymphoblastic leukemia	DC0VRBE	MOLT-4	Investigative	[18]
Anaplastic large cell lymphoma	DC1HCMI	SR	Investigative	[18]
Childhood T acute lymphoblastic leukemia	DC09HHD	CCRF-CEM	Investigative	[18]
Chronic myelogenous leukemia	DCC6K8Y	K-562	Investigative	[18]
Clear cell renal cell carcinoma	DC22SQP	TK-10	Investigative	[18]
Clear cell renal cell carcinoma	DC7TSFW	786-0	Investigative	[18]
Glioblastoma	DCA7TFM	SNB-75	Investigative	[18]
Glioma	DCIK646	SF-539	Investigative	[18]
Glioma	DCD9V8Q	SF-268	Investigative	[18]
Plasma cell myeloma	DCYSBJ0	RPMI-8226	Investigative	[18]
Renal cell carcinoma	DCOLUJ2	SN12C	Investigative	[18]
Breast adenocarcinoma	DCZHEKG	MDA-MB-468	Investigative	[19]
Carcinoma	DC51BBS	RXF 393	Investigative	[19]
Colon adenocarcinoma	DCPFTMU	COLO 205	Investigative	[19]
Colon carcinoma	DCBQOVE	KM12	Investigative	[19]
Invasive ductal carcinoma	DCIGNV8	HS 578T	Investigative	[19]
Invasive ductal carcinoma	DCCFFCC	BT-549	Investigative	[19]
Adenocarcinoma	DCE8N9U	NCIH23	Investigative	[1]
Adenocarcinoma	DCUM9M6	A549	Investigative	[1]
Adenocarcinoma	DCOUZUT	HCT116	Investigative	[1]
Adenocarcinoma	DC1D11H	SW-620	Investigative	[1]
Adenocarcinoma	DCRYFOB	HCC-2998	Investigative	[1]
Adenocarcinoma	DC3GRGR	HT29	Investigative	[1]
Amelanotic melanoma	DCVAQVT	M14	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCXINQ3	OVCAR-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCFPRDH	NCI\\/ADR-RES	Investigative	[1]
Large cell lung carcinoma	DCAUQ1P	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DCDWJ9S	HOP-62	Investigative	[1]
Lung adenocarcinoma	DC544CQ	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DCFK2GI	NCI-H522	Investigative	[1]
Malignant melanoma	DCBYAET	LOX IMVI	Investigative	[1]
Melanoma	DC0E3AZ	SK-MEL-2	Investigative	[1]
Pleural epithelioid mesothelioma	DCXL4SY	NCI-H226	Investigative	[1]
Prostate carcinoma	DC10ZO1	PC-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] 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. (Target id: 620).
• [6] Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res. 2012 Oct;160(4):298-308.
• [7] The role of P-glycoprotein in the bioactivation of raloxifene. Drug Metab Dispos. 2006 Dec;34(12):2073-8.
• [8] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [9] Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prev Res (Phila). 2013 Jul;6(7):719-30.
• [10] 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.
• [11] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [19] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165