Details of the Drug Combination

General Information of Drug Combination (ID: DCYHLZI)

• Drug Combination Name: Omacetaxine mepesuccinate + Primaquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  Omacetaxine mepesuccinate (DMPU2WX): Small molecular drug
  Primaquine (DMWQ16I): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 8.499
  Bliss Independence Score: 12.187
  Loewe Additivity Score: 6.173
  LHighest Single Agent (HSA) Score: 9.739

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Omacetaxine mepesuccinate

Disease Entry	ICD 11	Status	REF
Adult acute monocytic leukemia	N.A.	Approved	[2]
Chronic myelogenous leukaemia	2A20.0	Approved	[2]
Chronic myeloid leukaemia	2A20	Approved	[3]
Leukemia	N.A.	Approved	[2]

Omacetaxine mepesuccinate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Ribosome A (hRA)	TTA4FIU	NOUNIPROTAC	Modulator	[5]

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	[6]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[6]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Increases Expression	[7]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[8]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[7]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[7]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Increases Expression	[7]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Increases Expression	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[7]
Hematopoietic progenitor cell antigen CD34 (CD34)	OT1MOFLZ	CD34_HUMAN	Decreases Expression	[6]
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (CD38)	OTG0TTX7	CD38_HUMAN	Increases Expression	[6]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[7]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Expression	[7]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[7]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[7]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[7]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Increases Expression	[6]
Ephrin type-B receptor 4 (EPHB4)	OTKLPVXJ	EPHB4_HUMAN	Decreases Expression	[7]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Cleavage	[7]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[7]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[7]
Nuclear factor NF-kappa-B p100 subunit (NFKB2)	OTS231V7	NFKB2_HUMAN	Increases Expression	[6]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Increases Expression	[6]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Expression	[6]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[7]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[8]
Jouberin (AHI1)	OT8K2YWY	AHI1_HUMAN	Increases Expression	[9]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[7]

Indication(s) of Primaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]

Primaquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium Deoxyribonucleic acid (Malaria DNA)	TT698WO	NOUNIPROTAC	.	[10]

Primaquine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]

Primaquine Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[13]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[13]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[16]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[16]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[16]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[16]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[16]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[17]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[18]
Hemoglobin subunit gamma-2 (HBG2)	OT4J48JJ	HBG2_HUMAN	Increases Expression	[19]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[16]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Decreases Response To Substance	[20]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Metabolism	[19]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Metabolism	[19]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Metabolism	[19]

References

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• [2] Omacetaxine mepesuccinate 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: 7454).
• [4] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 008316.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] 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.
• [7] 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.
• [8] [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.
• [9] [Expression and function of Ahi-1 gene in Jurkat cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Apr;17(2):445-9.
• [10] Primaquine-induced differential gene expression analysis in mice liver using DNA microarrays. Toxicology. 2007 Sep 24;239(1-2):96-107.
• [11] Primaquine metabolism by human liver microsomes: effect of other antimalarial drugs. Biochem Pharmacol. 1992 Aug 4;44(3):587-90.
• [12] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [13] Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells. Eur J Clin Pharmacol. 2002 Nov;58(8):537-42.
• [14] Time-dependent transcriptional induction of CYP1A1, CYP1A2 and CYP1B1 mRNAs by H+/K+ -ATPase inhibitors and other xenobiotics. Xenobiotica. 2003 Feb;33(2):107-18.
• [15] 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.
• [16] 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.
• [17] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [18] 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.
• [19] Cytochrome P(450)-dependent toxic effects of primaquine on human erythrocytes. Toxicol Appl Pharmacol. 2009 Nov 15;241(1):14-22. doi: 10.1016/j.taap.2009.07.012. Epub 2009 Jul 17.
• [20] Understanding the mechanisms for metabolism-linked hemolytic toxicity of primaquine against glucose 6-phosphate dehydrogenase deficient human erythrocytes: evaluation of eryptotic pathway. Toxicology. 2012 Mar 29;294(1):54-60. doi: 10.1016/j.tox.2012.01.015. Epub 2012 Feb 6.