Details of the Drug Combination

General Information of Drug Combination (ID: DCXZGA7)

• Drug Combination Name: Pazopanib + Isoproterenol
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pazopanib (DMF57DM): N.A.
  Isoproterenol (DMK7MEY): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 17.9
  Bliss Independence Score: 17.9
  Loewe Additivity Score: 38.21
  LHighest Single Agent (HSA) Score: 38.21

Molecular Interaction Atlas of This Drug Combination

Pazopanib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[6]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[6]

Pazopanib Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[8]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Expression	[8]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[9]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[8]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[10]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[11]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[12]
Myeloblastin (PRTN3)	OT72MHP7	PRTN3_HUMAN	Increases Expression	[10]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[13]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[13]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[11]
HLA class I histocompatibility antigen protein P5 (HCP5)	OTV0YRI8	HCP5_HUMAN	Increases ADR	[14]

Indication(s) of Isoproterenol

Disease Entry	ICD 11	Status	REF
Atrioventricular block	N.A.	Approved	[2]
Cardiac arrest	MC82	Approved	[2]
Common cold	CA00	Approved	[2]
Heart block	BC63	Approved	[3]
Melanoma	2C30	Phase 1	[4]

Isoproterenol Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[16]
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Modulator	[16]
Interleukin-12 beta (IL12B)	TTGW72V	IL12B_HUMAN	Modulator	[17]

Isoproterenol Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[18]

Isoproterenol Interacts with 74 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[19]
Apoptotic protease-activating factor 1 (APAF1)	OTJWIVY0	APAF_HUMAN	Increases Expression	[15]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[15]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[15]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Decreases Expression	[15]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[15]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[15]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[15]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[15]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[15]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[15]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[15]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Decreases Expression	[15]
Heat shock cognate 71 kDa protein (HSPA8)	OTJI2RCI	HSP7C_HUMAN	Decreases Expression	[15]
Interleukin-7 (IL7)	OTT6YSKM	IL7_HUMAN	Increases Expression	[15]
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)	OT2D9DOV	TNR1A_HUMAN	Decreases Expression	[15]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[15]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Decreases Expression	[15]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[15]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Decreases Expression	[15]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Expression	[15]
Metalloproteinase inhibitor 3 (TIMP3)	OTDGQAD1	TIMP3_HUMAN	Increases Expression	[15]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Expression	[15]
Heat shock-related 70 kDa protein 2 (HSPA2)	OTSDET7B	HSP72_HUMAN	Increases Expression	[15]
C-C motif chemokine 7 (CCL7)	OTDIS99H	CCL7_HUMAN	Decreases Expression	[15]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Decreases Expression	[15]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[15]
Four and a half LIM domains protein 1 (FHL1)	OTN535SU	FHL1_HUMAN	Decreases Expression	[15]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[15]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Decreases Expression	[15]
Regenerating islet-derived protein 3-gamma (REG3G)	OTLIUY8Z	REG3G_HUMAN	Decreases Expression	[15]
Metalloproteinase inhibitor 4 (TIMP4)	OT8A68SW	TIMP4_HUMAN	Decreases Expression	[15]
Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2)	OTAQD3YV	ARNT2_HUMAN	Decreases Expression	[15]
Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN)	OT5LIL3W	HIF1N_HUMAN	Decreases Expression	[15]
Hypoxia-inducible factor 3-alpha (HIF3A)	OTPWAAMC	HIF3A_HUMAN	Increases Expression	[15]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[20]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Affects Binding	[21]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[22]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[23]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[24]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases Expression	[25]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Decreases Secretion	[26]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[20]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Decreases Expression	[24]
Transferrin receptor protein 1 (TFRC)	OT8ZPBDL	TFR1_HUMAN	Decreases Expression	[27]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[20]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases Expression	[28]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Expression	[29]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Increases Expression	[30]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[30]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Expression	[31]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[20]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Activity	[32]
Beta-3 adrenergic receptor (ADRB3)	OTPMG4V7	ADRB3_HUMAN	Increases Activity	[33]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[34]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[25]
Beta-adrenergic receptor kinase 1 (GRK2)	OT34KKWK	ARBK1_HUMAN	Increases Expression	[35]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[36]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[36]
Beta-arrestin-2 (ARRB2)	OTAEJZCI	ARRB2_HUMAN	Affects Localization	[37]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[20]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Secretion	[38]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[20]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[20]
C-C motif chemokine 17 (CCL17)	OTIKW21L	CCL17_HUMAN	Decreases Secretion	[39]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Phosphorylation	[40]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[20]
Interleukin-1 receptor antagonist protein (IL1RN)	OT308CBE	IL1RA_HUMAN	Affects Response To Substance	[41]
Dystroglycan 1 (DAG1)	OT6QBA05	DAG1_HUMAN	Increases ADR	[42]
Bone morphogenetic protein 10 (BMP10)	OTA3QKKG	BMP10_HUMAN	Decreases Response To Substance	[43]
Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL)	OTESDTEU	GNAL_HUMAN	Increases Response To Substance	[44]
Neuroendocrine secretory protein 55 (GNAS)	OTMH8BKJ	GNAS3_HUMAN	Increases Response To Substance	[44]
Interleukin-5 receptor subunit alpha (IL5RA)	OTMSLUG9	IL5RA_HUMAN	Affects Response To Substance	[41]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[45]

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] Isoproterenol FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 083346.
• [4] A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma. Clin Cancer Res. 2011 Apr 1;17(7):1998-2005.
• [5] Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer. 2010 Apr 27;102(9):1371-7. doi: 10.1038/sj.bjc.6605653. Epub 2010 Apr 13.
• [6] Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35.
• [7] Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54.
• [8] Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles. Arch Toxicol. 2018 Apr;92(4):1435-1451.
• [9] 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.
• [10] Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: Implications for VEGFR TKIs-induced immune related adverse events. Toxicol In Vitro. 2021 Mar;71:105063. doi: 10.1016/j.tiv.2020.105063. Epub 2020 Dec 1.
• [11] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [12] 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.
• [13] MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model. Br J Cancer. 2016 Oct 11;115(8):920-928. doi: 10.1038/bjc.2016.263. Epub 2016 Aug 25.
• [14] HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer. Clin Cancer Res. 2016 Mar 15;22(6):1371-7. doi: 10.1158/1078-0432.CCR-15-2044. Epub 2015 Nov 6.
• [15] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [16] Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404.
• [17] A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma. Clin Cancer Res. 2011 Apr 1;17(7):1998-2005.
• [18] Identification, characterization, and ontogenic study of a catechol O-methyltransferase from zebrafish. Aquat Toxicol. 2011 Mar;102(1-2):18-23.
• [19] Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression. Biochem Pharmacol. 2005 Jan 15;69(2):277-87.
• [20] 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.
• [21] Ligand binding and aggregation of pathogenic SOD1. Nat Commun. 2013;4:1758. doi: 10.1038/ncomms2750.
• [22] Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983 Dec 8;309(23):1414-9. doi: 10.1056/NEJM198312083092303.
• [23] Vascular renin-angiotensin system and neurotransmission in hypertensive persons. Hypertension. 1991 Sep;18(3):266-77. doi: 10.1161/01.hyp.18.3.266.
• [24] The regulation of human vascular smooth muscle extracellular matrix protein production by alpha- and beta-adrenoceptor stimulation. J Hypertens. 2002 Feb;20(2):287-94. doi: 10.1097/00004872-200202000-00019.
• [25] Low doses of BPF-induced hypertrophy in cardiomyocytes derived from human embryonic stem cells via disrupting the mitochondrial fission upon the interaction between ER and calcineurin A-DRP1 signaling pathway. Cell Biol Toxicol. 2022 Jun;38(3):409-426. doi: 10.1007/s10565-021-09615-y. Epub 2021 May 22.
• [26] Post-receptorial mechanisms underlie functional disregulation of beta2-adrenergic receptors in lymphocytes from Multiple Sclerosis patients. J Neuroimmunol. 2004 Oct;155(1-2):143-9. doi: 10.1016/j.jneuroim.2004.05.013.
• [27] Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression. J Immunol. 1985 Aug;135(2):1172-9.
• [28] The effects of desmethylimipramine on cyclic AMP-stimulated gene transcription in a model cell system. Biochem Pharmacol. 2005 Sep 1;70(5):762-9. doi: 10.1016/j.bcp.2005.06.012.
• [29] Isoproterenol inhibits angiotensin II-stimulated proliferation and reactive oxygen species production in vascular smooth muscle cells through heme oxygenase-1. Biol Pharm Bull. 2009 Jun;32(6):1047-52. doi: 10.1248/bpb.32.1047.
• [30] Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking ?-adrenergic signaling. Arch Biochem Biophys. 2014 Sep 1;557:18-27. doi: 10.1016/j.abb.2014.05.030. Epub 2014 Jun 11.
• [31] Impaired PARP activity in response to the -adrenergic receptor agonist isoproterenol. Toxicol In Vitro. 2018 Aug;50:29-39. doi: 10.1016/j.tiv.2018.02.001. Epub 2018 Feb 10.
• [32] Activation of airway cl- secretion in human subjects by adenosine. Am J Respir Cell Mol Biol. 2004 Aug;31(2):140-6. doi: 10.1165/rcmb.2004-0012OC. Epub 2004 Mar 23.
• [33] Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II. J Med Chem. 2008 Jul 10;51(13):4002-20. doi: 10.1021/jm8000345. Epub 2008 Jun 14.
• [34] Adrenoceptor blockade alters plasma gelatinase activity in patients with heart failure and MMP-9 promoter activity in a human cell line (ECV304). Pharmacol Res. 2006 Jul;54(1):57-64. doi: 10.1016/j.phrs.2006.02.006. Epub 2006 Feb 28.
• [35] Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade. Circulation. 1998 Oct 27;98(17):1783-9. doi: 10.1161/01.cir.98.17.1783.
• [36] A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. doi: 10.1073/pnas.0707936104. Epub 2007 Oct 9.
• [37] Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell. 2007 May 4;129(3):511-22. doi: 10.1016/j.cell.2007.02.046.
• [38] Catecholamines suppress leptin release from in vitro differentiated subcutaneous human adipocytes in primary culture via beta1- and beta2-adrenergic receptors. Eur J Endocrinol. 2000 Sep;143(3):439-45. doi: 10.1530/eje.0.1430439.
• [39] IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype. Am J Physiol Lung Cell Mol Physiol. 2003 Oct;285(4):L907-14. doi: 10.1152/ajplung.00120.2003. Epub 2003 Jul 18.
• [40] Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med. 2011 Jul 10;17(8):1003-9. doi: 10.1038/nm.2406.
• [41] Autocrine interaction between IL-5 and IL-1beta mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest. 1999 Sep;104(5):657-67. doi: 10.1172/JCI7137.
• [42] 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.
• [43] BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways. J Biol Chem. 2019 Dec 27;294(52):19877-19888. doi: 10.1074/jbc.RA119.010943. Epub 2019 Nov 11.
• [44] Identification of specific ligands for orphan olfactory receptors. G protein-dependent agonism and antagonism of odorants. J Biol Chem. 2005 Mar 25;280(12):11807-15. doi: 10.1074/jbc.M411508200. Epub 2004 Dec 14.
• [45] Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.