Details of the Drug Combination

General Information of Drug Combination (ID: DC7F9HT)

• Drug Combination Name: Lenalidomide + Mepacrine
• Indication: Renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Lenalidomide (DM6Q7U4): Small molecular drug
  Mepacrine (DMU8L7C): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: UO-31
  Zero Interaction Potency (ZIP) Score: 5.34
  Bliss Independence Score: 13.93
  Loewe Additivity Score: 10.68
  LHighest Single Agent (HSA) Score: 12.74

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lenalidomide

Disease Entry	ICD 11	Status	REF
Adult T-cell leukemia/lymphoma	N.A.	Approved	[2]
Advanced cancer	2A00-2F9Z	Approved	[2]
Complex regional pain syndrome type 1	N.A.	Approved	[2]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[2]
Large granular lymphocytic leukemia	2A90.1	Approved	[2]
Leukemia	N.A.	Approved	[2]
MALT lymphoma	N.A.	Approved	[2]
Multiple myeloma	2A83	Approved	[3]
Nodal marginal zone lymphoma	2A85.0	Approved	[2]
Pain	MG30-MG3Z	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[2]
Prolymphocytic leukaemia	2A82.1	Approved	[2]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[2]
Small intestine lymphoma	N.A.	Approved	[2]
Splenic marginal zone lymphoma	N.A.	Approved	[2]
Testicular lymphoma	N.A.	Approved	[2]
Urinary bladder neoplasm	N.A.	Approved	[2]
Waldenstrom macroglobulinemia	2A85.4	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Colon cancer	2B90.Z	Investigative	[2]

Lenalidomide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	TTF8CQI	TNFA_HUMAN	Inhibitor	[6]

Lenalidomide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Lenalidomide Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)	OT2D9DOV	TNR1A_HUMAN	Decreases Expression	[8]
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B)	OTDS2EAR	TNR1B_HUMAN	Decreases Expression	[8]
Interleukin-6 receptor subunit beta (IL6ST)	OT1N9C70	IL6RB_HUMAN	Decreases Expression	[8]
DNA damage-binding protein 1 (DDB1)	OTTR2L3Z	DDB1_HUMAN	Affects Binding	[9]
Sal-like protein 4 (SALL4)	OTC08PR5	SALL4_HUMAN	Affects Binding	[10]

Indication(s) of Mepacrine

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[5]

Mepacrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phospholipase A2 (PLA2G1B)	TT9V5JH	PA21B_HUMAN	Inhibitor	[5]

Mepacrine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]

Mepacrine 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 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]

Mepacrine Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[13]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[14]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1)	OTSBQR6D	PLCG1_HUMAN	Decreases Phosphorylation	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[14]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[14]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[16]
Casein kinase I isoform alpha (CSNK1A1)	OTJ6O1IC	KC1A_HUMAN	Increases Expression	[13]
Forkhead box protein P3 (FOXP3)	OTA9Z9OC	FOXP3_HUMAN	Increases Expression	[14]
F-box/WD repeat-containing protein 1A (BTRC)	OT2EZDGR	FBW1A_HUMAN	Decreases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[12]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Colon carcinoma	DCC15YH	KM12	Investigative	[17]
High grade ovarian serous adenocarcinoma	DCXGNKR	OVCAR-8	Investigative	[18]
Pleural epithelioid mesothelioma	DCPDJFR	NCI-H226	Investigative	[18]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Lenalidomide FDA Label
• [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: 7331).
• [4] Low-dose Lenalidomide for Non-severe COVID-19 Treatment Trial (GETAFE)
• [5] Involvement of protein kinase C activation in L-leucine-induced stimulation of protein synthesis in l6 myotubes. Cytotechnology. 2003 Nov;43(1-3):97-103.
• [6] Thalidomide and thalidomide analogues for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007351.
• [7] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB00480)
• [8] Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005 Apr 15;105(8):3286-94. doi: 10.1182/blood-2004-06-2101. Epub 2004 Dec 23.
• [9] Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014 Sep;21(9):803-9. doi: 10.1038/nsmb.2874. Epub 2014 Aug 10.
• [10] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [11] Arginine-482 is not essential for transport of antibiotics, primary bile acids and unconjugated sterols by the human breast cancer resistance protein (ABCG2). Biochem J. 2005 Jan 15;385(Pt 2):419-26.
• [12] Quinacrine is mainly metabolized to mono-desethyl quinacrine by CYP3A4/5 and its brain accumulation is limited by P-glycoprotein. Drug Metab Dispos. 2006 Jul;34(7):1136-44.
• [13] Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and catenin through activation of GSK3. Toxicol Appl Pharmacol. 2017 Sep 1;330:53-64. doi: 10.1016/j.taap.2017.07.008. Epub 2017 Jul 15.
• [14] Quinacrine induces the apoptosis of human leukemia U937 cells through FOXP3/miR-183/-TrCP/SP1 axis-mediated BAX upregulation. Toxicol Appl Pharmacol. 2017 Nov 1;334:35-46. doi: 10.1016/j.taap.2017.08.019. Epub 2017 Sep 1.
• [15] Quinacrine is active in preclinical models of glioblastoma through suppressing angiogenesis, inducing oxidative stress and activating AMPK. Toxicol In Vitro. 2022 Sep;83:105420. doi: 10.1016/j.tiv.2022.105420. Epub 2022 Jun 17.
• [16] Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action. Arch Toxicol. 2021 Jan;95(1):321-336. doi: 10.1007/s00204-020-02902-3. Epub 2020 Sep 10.
• [17] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [18] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976