Details of the Drug Combination

General Information of Drug Combination (ID: DC168S3)

• Drug Combination Name: Acetazolamide + Everolimus
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Acetazolamide (DM1AF5U): Small molecular drug
  Everolimus (DM8X2EH): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 9.76
  Bliss Independence Score: 9.76
  Loewe Additivity Score: 15.76
  LHighest Single Agent (HSA) Score: 15.81

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Acetazolamide

Disease Entry	ICD 11	Status	REF
Absence epilepsy	N.A.	Approved	[2]
Altitude sickness	N.A.	Approved	[2]
Edema	MG29	Approved	[2]
Glaucoma/ocular hypertension	9C61	Approved	[3]

Acetazolamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Carbonic anhydrase I (CA-I)	TTHQPL7	CAH1_HUMAN	Modulator	[9]

Acetazolamide Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Carbonic anhydrase 12 (CA12)	OT6WNFU8	CAH12_HUMAN	Decreases Activity	[10]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Decreases Activity	[11]
Carbonic anhydrase 9 (CA9)	OTNA51XT	CAH9_HUMAN	Decreases Activity	[10]
Aquaporin-1 (AQP1)	OTX5MYX9	AQP1_HUMAN	Decreases Expression	[12]
Rho GTPase-activating protein 45 (ARHGAP45)	OTL86FEQ	HMHA1_HUMAN	Affects Expression	[13]
Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R)	OTQF5ZAK	PTH1R_HUMAN	Increases ADR	[14]

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[4]
Advanced/metastatic breast cancer	2C60	Approved	[5]
Brainstem neoplasm	N.A.	Approved	[4]
Breast carcinoma	N.A.	Approved	[4]
Graft-versus-host disease	4B24	Approved	[4]
Intracranial meningioma	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Mucosal melanoma	N.A.	Approved	[4]
Multiple sclerosis	8A40	Approved	[4]
Plasma cell myeloma	2A83.1	Approved	[4]
Prostate cancer	2C82.0	Approved	[4]
Renal cell carcinoma	2C90	Approved	[6]
Salivary gland squamous cell carcinoma	N.A.	Approved	[4]
Tuberous sclerosis	LD2D.2	Approved	[4]
Kidney cancer	2C90.0	Phase 3	[6]
Castration-resistant prostate carcinoma	N.A.	Investigative	[4]
Colon cancer	2B90.Z	Investigative	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[7]
Neuroblastoma	2D11.2	Investigative	[4]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[4]
Polycystic kidney disease	GB8Y	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[7]

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	[15]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[7]

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	[16]

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	[17]

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] Acetazolamide 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: 6792).
• [4] Everolimus FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] 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).
• [7] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [8] Tamm-Horsfall protein accumulation in glomeruli during acetazolamide-induced acute renal failure. Am J Nephrol. 1989;9(1):56-7. doi: 10.1159/000167936.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [10] Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors. J Med Chem. 2011 Oct 13;54(19):6905-18.
• [11] Indomethacin activates carbonic anhydrase and antagonizes the effect of the specific carbonic anhydrase inhibitor acetazolamide, by a direct mechanism of action. Int J Clin Pharmacol Ther. 2001 Jun;39(6):265-70.
• [12] [Effect of inhibiting aquaporin-1 on proliferation and apoptosis of the Hep-2 cell]. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2006 Nov;20(21):988-91.
• [13] 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.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [15] 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.
• [16] 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.
• [17] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.