Details of the Drug Combination

General Information of Drug Combination (ID: DC6B5PM)

• Drug Combination Name: Diltiazem + Omacetaxine mepesuccinate
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Diltiazem (DMAI7ZV): Small molecular drug
  Omacetaxine mepesuccinate (DMPU2WX): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 5.707
  Bliss Independence Score: 6.584
  Loewe Additivity Score: 2.776
  LHighest Single Agent (HSA) Score: 7.17

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Diltiazem

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Atrial fibrillation	BC81.3	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]

Diltiazem Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated calcium channel alpha-2/delta-1 (CACNA2D1)	TTFK1JQ	CA2D1_HUMAN	Blocker	[6]

Diltiazem 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]

Diltiazem Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[12]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]

Diltiazem Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[14]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[14]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[14]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Increases Response	[15]
Potassium voltage-gated channel subfamily E member 1 (KCNE1)	OTZNQUW9	KCNE1_HUMAN	Increases ADR	[14]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Increases ADR	[14]

Indication(s) of Omacetaxine mepesuccinate

Disease Entry	ICD 11	Status	REF
Adult acute monocytic leukemia	N.A.	Approved	[4]
Chronic myelogenous leukaemia	2A20.0	Approved	[4]
Chronic myeloid leukaemia	2A20	Approved	[5]
Leukemia	N.A.	Approved	[4]

Omacetaxine mepesuccinate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Ribosome A (hRA)	TTA4FIU	NOUNIPROTAC	Modulator	[16]

Omacetaxine mepesuccinate Interacts with 29 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK)	OTLF4ZB1	IKKA_HUMAN	Increases Phosphorylation	[17]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[17]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Increases Expression	[18]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[19]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[18]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[18]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Increases Expression	[18]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Increases Expression	[18]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[18]
Hematopoietic progenitor cell antigen CD34 (CD34)	OT1MOFLZ	CD34_HUMAN	Decreases Expression	[17]
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (CD38)	OTG0TTX7	CD38_HUMAN	Increases Expression	[17]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[18]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Expression	[18]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[18]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[18]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[18]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Increases Expression	[17]
Ephrin type-B receptor 4 (EPHB4)	OTKLPVXJ	EPHB4_HUMAN	Decreases Expression	[18]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Cleavage	[18]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[18]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[18]
Nuclear factor NF-kappa-B p100 subunit (NFKB2)	OTS231V7	NFKB2_HUMAN	Increases Expression	[17]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Increases Expression	[17]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Expression	[17]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[18]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[19]
Jouberin (AHI1)	OT8K2YWY	AHI1_HUMAN	Increases Expression	[20]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
DD2	DCIMJPF	DD2	Investigative	[21]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [2] Diltiazem 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: 2298).
• [4] Omacetaxine mepesuccinate FDA Label
• [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: 7454).
• [6] Egr-1, the potential target of calcium channel blockers in cardioprotection with ischemia/reperfusion injury in rats. Cell Physiol Biochem. 2009;24(1-2):17-24.
• [7] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [8] Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002 Aug;30(8):883-91.
• [9] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [10] Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients. J Clin Pharm Ther. 2016 Jun;41(3):341-7.
• [11] FDA Drug Development and Drug Interactions
• [12] Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther. 1997 Jul;282(1):294-300.
• [13] Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Drug Metab Dispos. 2001 Oct;29(10):1284-9.
• [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] A common 1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. J Am Coll Cardiol. 2012 Jan 3;59(1):49-56. doi: 10.1016/j.jacc.2011.08.061.
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [17] Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms. J Exp Clin Cancer Res. 2019 Jul 15;38(1):308. doi: 10.1186/s13046-019-1295-8.
• [18] Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways. Food Chem Toxicol. 2020 Feb;136:110960. doi: 10.1016/j.fct.2019.110960. Epub 2019 Nov 11.
• [19] [Homoharringtonine combined arsenic trioxide induced apoptosis in human multiple myeloma cell line RPMI 8226: an experimental research]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013 Jun;33(6):834-9.
• [20] [Expression and function of Ahi-1 gene in Jurkat cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Apr;17(2):445-9.
• [21] 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.