Details of the Drug Combination

General Information of Drug Combination (ID: DCJMECB)

• Drug Combination Name: Lapatinib + Mepacrine
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Lapatinib (DM3BH1Y): Small molecular drug
  Mepacrine (DMU8L7C): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: OVCAR3
  Zero Interaction Potency (ZIP) Score: 0.74
  Bliss Independence Score: 4
  Loewe Additivity Score: 4.43
  LHighest Single Agent (HSA) Score: 4.83

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lapatinib

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Gastroesophageal junction adenocarcinoma	2B71	Approved	[3]
Melanoma	2C30	Approved	[3]

Lapatinib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[6]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[6]
Eukaryotic elongation factor 2 kinase (eEF-2K)	TT1QFLA	EF2K_HUMAN	Inhibitor	[7]

Lapatinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]

Lapatinib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Lapatinib Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[14]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[16]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[17]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Decreases Activity	[18]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Activity	[15]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Activity	[15]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[19]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1)	OTC6GISG	DQA1_HUMAN	Increases ADR	[20]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Decreases Response To Substance	[21]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Response To Substance	[21]
Tenascin-X (TNXB)	OTVBWAV5	TENX_HUMAN	Increases ADR	[20]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Increases ADR	[20]

Indication(s) of Mepacrine

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[4]

Mepacrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phospholipase A2 (PLA2G1B)	TT9V5JH	PA21B_HUMAN	Inhibitor	[4]

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	[22]

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	[23]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[23]

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	[24]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[25]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1)	OTSBQR6D	PLCG1_HUMAN	Decreases Phosphorylation	[26]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[25]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[25]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[24]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[27]
Casein kinase I isoform alpha (CSNK1A1)	OTJ6O1IC	KC1A_HUMAN	Increases Expression	[24]
Forkhead box protein P3 (FOXP3)	OTA9Z9OC	FOXP3_HUMAN	Increases Expression	[25]
F-box/WD repeat-containing protein 1A (BTRC)	OT2EZDGR	FBW1A_HUMAN	Decreases Expression	[25]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[23]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
• [2] 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: 5692).
• [3] Lapatinib FDA Label
• [4] 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.
• [5] UGT-dependent regioselective glucuronidation of ursodeoxycholic acid and obeticholic acid and selective transport of the consequent acyl glucuronides by OATP1B1 and 1B3. Chem Biol Interact. 2019 Sep 1;310:108745. doi: 10.1016/j.cbi.2019.108745. Epub 2019 Jul 9.
• [6] Triple negative breast cancer--current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009 Mar;153(1):13-7.
• [7] Inhibition of eEF-2 kinase sensitizes human nasopharyngeal carcinoma cells to lapatinib-induced apoptosis through the Src and Erk pathways.BMC Cancer. 2016 Oct 19;16(1):813.
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• [9] The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos. 2008 Apr;36(4):695-701.
• [10] Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703.
• [11] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [12] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [13] P450 3A-catalyzed O-dealkylation of lapatinib induces mitochondrial stress and activates Nrf2. Chem Res Toxicol. 2016 May 16;29(5):784-96.
• [14] Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene. 2005 Sep 15;24(41):6213-21. doi: 10.1038/sj.onc.1208774.
• [15] CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer. 2014 Jul;5(7-8):261-72. doi: 10.18632/genesandcancer.24.
• [16] The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib. Toxicol Sci. 2023 Dec 21;197(1):69-78. doi: 10.1093/toxsci/kfad099.
• [17] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [18] Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res. 2009 Jun 15;15(12):4147-56. doi: 10.1158/1078-0432.CCR-08-2814. Epub 2009 Jun 9.
• [19] The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 2005 Jan 1;65(1):18-25.
• [20] HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011 Feb 20;29(6):667-73. doi: 10.1200/JCO.2010.31.3197. Epub 2011 Jan 18.
• [21] Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer. Int J Biochem Cell Biol. 2016 Feb;71:12-23. doi: 10.1016/j.biocel.2015.11.014. Epub 2015 Nov 28.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
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