Details of the Drug Combination

General Information of Drug Combination (ID: DCS8OSN)

• Drug Combination Name: Sirolimus + Lapatinib
• Indication: Cutaneous melanoma; Status: Investigative [1]
• Component Drugs:
  Sirolimus (DMGW1ID): Small molecular drug
  Lapatinib (DM3BH1Y): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SK-MEL-28
  Zero Interaction Potency (ZIP) Score: 4.86
  Bliss Independence Score: 6.97
  Loewe Additivity Score: 4.41
  LHighest Single Agent (HSA) Score: 3.79

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sirolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Brainstem neoplasm	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Lung lymphangioleiomyomatosis	N.A.	Approved	[2]
Lymphangioleiomyomatosis	CB07	Approved	[3]
Mucosal melanoma	N.A.	Approved	[2]
Multiple myeloma	2A83	Approved	[4]
Multiple sclerosis	8A40	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Organ transplant rejection	NE84	Approved	[5]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Uveitis	9A96.Z	Phase 3	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Dutch elm disease	8D64	Phase 1/2	[5]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Rheumatoid arthritis	FA20	Investigative	[2]

Sirolimus Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[10]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[11]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[12]

Sirolimus Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[14]

Sirolimus Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]

Sirolimus Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[17]

Indication(s) of Lapatinib

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[8]
Gastroesophageal junction adenocarcinoma	2B71	Approved	[9]
Melanoma	2C30	Approved	[9]

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	[19]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[19]
Eukaryotic elongation factor 2 kinase (eEF-2K)	TT1QFLA	EF2K_HUMAN	Inhibitor	[20]

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	[21]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[22]

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	[23]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[24]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[23]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[24]

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	[25]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[26]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[27]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[28]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[29]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[30]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Decreases Activity	[31]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Activity	[28]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Activity	[28]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[32]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1)	OTC6GISG	DQA1_HUMAN	Increases ADR	[33]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Decreases Response To Substance	[34]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Response To Substance	[34]
Tenascin-X (TNXB)	OTVBWAV5	TENX_HUMAN	Increases ADR	[33]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Increases ADR	[33]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Anaplastic large cell lymphoma	DCCMSKL	SR	Investigative	[35]
Astrocytoma	DCX6X2A	SNB-19	Investigative	[35]
Chronic myelogenous leukemia	DC81Q64	K-562	Investigative	[35]
Clear cell renal cell carcinoma	DC8DFRJ	A498	Investigative	[35]
Clear cell renal cell carcinoma	DCKVHNO	786-0	Investigative	[35]
Clear cell renal cell carcinoma	DCC5VXQ	CAKI-1	Investigative	[35]
Papillary renal cell carcinoma	DCHH364	ACHN	Investigative	[35]
Plasma cell myeloma	DCXOLH6	RPMI-8226	Investigative	[35]
Renal cell carcinoma	DC9AMY8	UO-31	Investigative	[35]
Breast adenocarcinoma	DCUR8MW	MDA-MB-468	Investigative	[36]
Colon adenocarcinoma	DCMO56E	COLO 205	Investigative	[36]
Colon carcinoma	DCDD7CT	KM12	Investigative	[36]
Invasive ductal carcinoma	DCWZ6D1	HS 578T	Investigative	[36]
Invasive ductal carcinoma	DC0KKYA	BT-549	Investigative	[36]
Adenocarcinoma	DCU1ARS	DU-145	Investigative	[1]
Adenocarcinoma	DCVR78D	OVCAR3	Investigative	[1]
Adenocarcinoma	DCQPO9W	NCIH23	Investigative	[1]
Adenocarcinoma	DC2T1AX	A549	Investigative	[1]
Adenocarcinoma	DC8LNN6	SW-620	Investigative	[1]
Adenocarcinoma	DCS4QIF	HCC-2998	Investigative	[1]
Adenocarcinoma	DCVYQDD	HCT-15	Investigative	[1]
Adenocarcinoma	DC3ONFW	HCT116	Investigative	[1]
Lung adenocarcinoma	DCA0IKM	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DCLV9UI	EKVX	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DC32URJ	IGROV1	Investigative	[1]
Prostate carcinoma	DCPHZ5A	PC-3	Investigative	[1]

References

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• [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. (Ligand id: 6031).
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] ClinicalTrials.gov (NCT04341675) Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia. U.S. National Institutes of Health.
• [8] 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).
• [9] Lapatinib FDA Label
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• [27] 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.
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