Details of the Drug Combination

General Information of Drug Combination (ID: DCWVGZ1)

• Drug Combination Name: Everolimus + Ethambutol
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Everolimus (DM8X2EH): Small molecular drug
  Ethambutol (DMR87LC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 12.59
  Bliss Independence Score: 12.59
  Loewe Additivity Score: 18.01
  LHighest Single Agent (HSA) Score: 18.01

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Advanced/metastatic breast cancer	2C60	Approved	[3]
Brainstem neoplasm	N.A.	Approved	[2]
Breast carcinoma	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Leukemia	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mucosal melanoma	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Renal cell carcinoma	2C90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Tuberous sclerosis	LD2D.2	Approved	[2]
Kidney cancer	2C90.0	Phase 3	[4]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Colon cancer	2B90.Z	Investigative	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[5]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[5]

Everolimus Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[6]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[5]

Everolimus 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]

Everolimus Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]

Indication(s) of Ethambutol

Disease Entry	ICD 11	Status	REF
Pulmonary tuberculosis	1B10.Z	Approved	[3]

Ethambutol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mycobacterium Arabinosyltransferase C (MycB embC)	TT1Q8GP	EMBC_MYCTU	Inhibitor	[9]

Ethambutol Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[10]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[10]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[10]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[10]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[11]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Secretion	[12]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[13]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[13]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[13]
Granzyme B (GZMB)	OTPPVIRS	GRAB_HUMAN	Increases Secretion	[12]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[13]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[13]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Increases Secretion	[12]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[13]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[11]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[13]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Everolimus FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] 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: 5889).
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
• [7] Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations. Ther Drug Monit. 2015 Oct;37(5):675-80.
• [8] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.
• [9] The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2009 Oct;53(10):4138-46.
• [10] Inhibition of cytochrome P450 by ethambutol in human liver microsomes. Toxicol Lett. 2014 Aug 17;229(1):33-40.
• [11] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [12] Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury. Chem Res Toxicol. 2016 Nov 21;29(11):1793-1795. doi: 10.1021/acs.chemrestox.6b00393. Epub 2016 Nov 9.
• [13] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.