Details of the Drug Combination

General Information of Drug Combination (ID: DCCTNYH)

• Drug Combination Name: HKI-272 + Loperamide
• Indication: Early Stage HER2+ Breast Cancer; Status: Phase 2 [1]
• Component Drugs:
  HKI-272 (DM6QOVN): Small molecular drug
  Loperamide (DMOJZQ9): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of HKI-272

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[2]

HKI-272 Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[6]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[7]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[7]
ERBB2 messenger RNA (HER2 mRNA)	TTR5TV4	ERBB2_HUMAN	Inhibitor	[8]

HKI-272 Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]

HKI-272 Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[10]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[11]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[12]

Indication(s) of Loperamide

Disease Entry	ICD 11	Status	REF
Diarrhea	ME05.1	Approved	[3]
Traveler's diarrhea	ME05.1	Approved	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[5]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[5]

Loperamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor delta (OPRD1)	TT27RFC	OPRD_HUMAN	Binder	[13]

Loperamide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]

Loperamide Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[16]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[16]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[16]
Oxygen-insensitive NADPH nitroreductase A (nfsA)	DEDPI65	NFSA_ECOLI	Metabolism	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
HER2 Amplified Breast Cancer	DCS2X5I	N. A.	Phase 2	[18]

References

• [1] ClinicalTrials.gov (NCT02400476) An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021154)
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Loperamide FDA Label
• [5] Screening of an FDA-approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture Antimicrob Agents Chemother. 2014 Aug;58(8):4875-84.
• [6] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [7] Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cyst... Bioorg Med Chem. 2007 Jun 1;15(11):3635-48.
• [8] Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41.
• [9] Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):947-57.
• [10] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [11] Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
• [12] Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
• [13] Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8.
• [14] In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos. 2008 Feb;36(2):268-75.
• [15] Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8.
• [16] Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81.
• [17] Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans. Drug Metab Dispos. 1995 Mar;23(3):354-62.
• [18] ClinicalTrials.gov (NCT04366713) A Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib