Details of the Drug Combination

General Information of Drug Combination (ID: DCR72MH)

• Drug Combination Name: Regorafenib + Perindopril
• Indication: Metastatic Colorectal Cancer; Status: Phase 2 [1]
• Component Drugs:
  Regorafenib (DMHSY1I): Small molecular drug
  Perindopril (DMOPZDT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Regorafenib

Disease Entry	ICD 11	Status	REF
Gastrointestinal stromal tumour	2B5B	Approved	[2]
Metastasis from malignant tumor of colon	N.A.	Approved	[2]
Metastatic colorectal cancer	2B91	Approved	[3]

Regorafenib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Modulator	[6]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Modulator	[6]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Modulator	[6]

Regorafenib Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[7]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[7]

Regorafenib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[10]

Regorafenib Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[5]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[5]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[11]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[5]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Activity	[5]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[5]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[5]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Activity	[5]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[5]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[5]

Indication(s) of Perindopril

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[4]

Perindopril Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[13]

Perindopril Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[14]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[14]

Perindopril Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Affects Response To Substance	[15]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[16]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[16]
Kininogen-1 (KNG1)	OT4X9LDE	KNG1_HUMAN	Decreases Expression	[17]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[18]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[18]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[18]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[18]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[18]
Secreted frizzled-related protein 4 (SFRP4)	OT8PQUVB	SFRP4_HUMAN	Affects Binding	[19]
Type-1 angiotensin II receptor (AGTR1)	OT2NRMJP	AGTR1_HUMAN	Affects Response To Substance	[20]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[21]

References

• [1] ClinicalTrials.gov (NCT02651415) Phase II Study of Perindopril and Regorafenib in mCRC
• [2] Regorafenib 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: 5891).
• [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: 6367).
• [5] Regorefenib induces extrinsic/intrinsic apoptosis and inhibits MAPK/NF-B-modulated tumor progression in bladder cancer in vitro and in vivo. Environ Toxicol. 2019 Jun;34(6):679-688. doi: 10.1002/tox.22734. Epub 2019 Feb 25.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull. 2015;38(4):582-6.
• [8] Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res. 2015 Jul;32(7):2205-16.
• [9] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01913)
• [10] FDA Label of Regorafenib. The 2020 official website of the U.S. Food and Drug Administration.
• [11] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [12] Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. Circ J. 2002 Sep;66(9):811-5. doi: 10.1253/circj.66.811.
• [13] Fixed combination perindopril-amlodipine (Coveram) in the treatment of hypertension and coronary heart disease. Rev Med Liege. 2009 Apr;64(4):223-7.
• [14] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [15] ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus. Nephrol Dial Transplant. 2000 Oct;15(10):1617-23. doi: 10.1093/ndt/15.10.1617.
• [16] Experience with perindopril in normal volunteers. Arch Mal Coeur Vaiss. 1989 May;82 Spec No 1:35-41.
• [17] Long-term treatment with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease. Jpn J Pharmacol. 2002 Jan;88(1):100-7. doi: 10.1254/jjp.88.100.
• [18] The effects of 1 month antihypertensive treatment with perindopril, bisoprolol or both on the ex vivo ability of monocytes to secrete inflammatory cytokines. Int J Clin Pharmacol Ther. 2009 Nov;47(11):686-94. doi: 10.5414/cpp47686.
• [19] Computer aided screening of secreted frizzled-related protein 4 (SFRP4): a potential control for diabetes mellitus. Molecules. 2014 Jul 11;19(7):10129-36. doi: 10.3390/molecules190710129.
• [20] Influence of the angiotensin II type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension. 1996 Dec;28(6):1081-4. doi: 10.1161/01.hyp.28.6.1081.
• [21] 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.