Details of the Drug Combination

General Information of Drug Combination (ID: DC3YR8Q)

• Drug Combination Name: Raloxifene + Chlorambucil
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Raloxifene (DMDKF3M): Small molecular drug
  Chlorambucil (DMRKE63): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HT29
  Zero Interaction Potency (ZIP) Score: 6.3
  Bliss Independence Score: 8.62
  Loewe Additivity Score: 2.1
  LHighest Single Agent (HSA) Score: 1.35

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 Chlorambucil

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[3]
Small lymphocytic lymphoma	2A82.0	Approved	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]
Follicular lymphoma	2A80	Investigative	[4]

Chlorambucil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA replication (DNA repli)	TTABD5E	NOUNIPROTAC	Intercalator	[10]

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	[11]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[12]

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	[13]

Chlorambucil Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[14]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Expression	[15]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Expression	[15]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[15]
F-box only protein 30 (FBXO30)	OTD1P6LA	FBX30_HUMAN	Decreases Expression	[15]
Histone chaperone ASF1A (ASF1A)	OT4S44GP	ASF1A_HUMAN	Decreases Expression	[15]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Affects Expression	[16]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[17]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Affects Expression	[18]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[19]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[20]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[21]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[22]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[23]
Histone H4 (H4C1)	OTB71W46	H4_HUMAN	Decreases Expression	[20]
kinase isozyme 4, mitochondrial (PDK4)	OTCMHMBZ	PDK4_HUMAN	Affects Expression	[24]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[18]
Fanconi anemia group G protein (FANCG)	OT7MC8TZ	FANCG_HUMAN	Increases Response To Substance	[25]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[26]
Fanconi anemia group C protein (FANCC)	OTTIDM3P	FANCC_HUMAN	Increases Response To Substance	[25]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Clear cell renal cell carcinoma	DCE4KE4	CAKI-1	Investigative	[27]
Glioma	DCB4NKV	SF-295	Investigative	[27]
Papillary renal cell carcinoma	DCUKUEO	ACHN	Investigative	[27]
Invasive ductal carcinoma	DCGOMH4	BT-549	Investigative	[28]
Adenocarcinoma	DCD0K7C	DU-145	Investigative	[1]
Adenocarcinoma	DC5QGL6	NCIH23	Investigative	[1]
Cutaneous melanoma	DC02QSM	SK-MEL-28	Investigative	[1]
Lung adenocarcinoma	DCFZEGY	HOP-62	Investigative	[1]
Malignant melanoma	DCBT3W2	UACC62	Investigative	[1]
Melanoma	DCC3ITE	MALME-3M	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: 7143).
• [4] Chlorambucil FDA Label
• [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).
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• [12] Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004;44:137-66.
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• [19] Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells. Blood. 1996 Sep 15;88(6):2172-82.
• [20] A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate. Cell Cycle. 2006 Jul;5(14):1537-48. doi: 10.4161/cc.5.14.2913. Epub 2006 Jul 17.
• [21] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [22] 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.
• [23] 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.
• [24] 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.
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