Details of the Drug Combination

General Information of Drug Combination (ID: DCM4LRJ)

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

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[10]

Indication(s) of Budesonide

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[3]
Asthma	CA23	Approved	[4]
Crohn disease	DD70	Approved	[3]
Inflammatory bowel disease	DD72	Approved	[3]
Radiation proctitis	N.A.	Approved	[3]
Ulcerative colitis	DD71	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[5]

Budesonide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor (NR3C1)	TTYRL6O	GCR_HUMAN	Antagonist	[12]

Budesonide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[14]

Budesonide Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Organic solute transporter subunit alpha (SLC51A)	OTDJRZ0P	OSTA_HUMAN	Increases Expression	[15]
Organic solute transporter subunit beta (SLC51B)	OT4WYPSR	OSTB_HUMAN	Increases Expression	[15]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[16]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[17]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Decreases Expression	[18]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[19]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[11]
Eosinophil cationic protein (RNASE3)	OTVE2XD1	ECP_HUMAN	Decreases Expression	[20]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[11]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[11]
Interleukin-4 receptor subunit alpha (IL4R)	OTTXOTCW	IL4RA_HUMAN	Decreases Expression	[21]

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] Budesonide FDA Label
• [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: 7434).
• [5] Inhaled Corticosteroid Treatment of COVID19 Patients With Pneumonia
• [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] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [12] PXR-mediated induction of human CYP3A4 and mouse Cyp3a11 by the glucocorticoid budesonide. Eur J Pharm Sci. 2009 Mar 2;36(4-5):565-71.
• [13] No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology. 2005 Mar;41(3):595-602.
• [14] Sulfation of budesonide by human cytosolic sulfotransferase, dehydroepiandrosterone-sulfotransferase (DHEA-ST). Drug Metab Dispos. 2002 May;30(5):582-5.
• [15] Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos. 2009 Jul;30(5):241-58.
• [16] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [17] Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
• [18] The effects of inhaled glucocorticoids on bone mass and biochemical markers of bone homeostasis: a 1-year study of beclomethasone versus budesonide. Neth J Med. 1997 Jun;50(6):233-7. doi: 10.1016/s0300-2977(96)00081-2.
• [19] Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012 May 1;260(3):294-302. doi: 10.1016/j.taap.2012.03.008. Epub 2012 Mar 23.
• [20] Effects of different anti-asthmatic agents on induced sputum and eosinophil cationic protein in mild asthmatics. Respirology. 2004 Nov;9(4):514-20. doi: 10.1111/j.1440-1843.2004.00631.x.
• [21] Effect of inhaled corticosteroid on an immunoreactive thymus and activation-regulated chemokine expression in the bronchial biopsies from asthmatics. Allergy. 2005 Mar;60(3):317-22. doi: 10.1111/j.1398-9995.2005.00694.x.