Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DM6QOVN)

• Drug Name: HKI-272 Drug Info
• Synonyms: Neratinib (ERBB2 inhibitor)

Indication

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[1]

• Therapeutic Class: Anticancer Agents
• Cross-matching ID:
  PubChem CID: 9915743
  ChEBI ID: CHEMBL61397
  CAS Number: CAS 698387-09-6
  TTD Drug ID: DM6QOVN
  INTEDE Drug ID: DR1887
  ACDINA Drug ID: D00463

Molecule-Related Drug Atlas

Drug(s) Targeting Erbb2 tyrosine kinase receptor (HER2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lapatinib	DM3BH1Y	Breast cancer	2C60-2C65	Approved	[7]
Dacomitinib	DMOH8VY	Non-small-cell lung cancer	2C25.Y	Approved	[8]
BIBW 2992	DMTKD7Q	Non-small-cell lung cancer	2C25.Y	Approved	[9]
Merimepodib	DM0HS92	Breast cancer	2C60-2C65	Approved	[10]
NERATINIB MALEATE	DMEDU7B	HER2/NEU overexpressing breast cancer	2C60-2C65	Approved	[11]
Margetuximab	DMKEY6S	HER2-positive breast cancer	2C60-2C65	Approved	[12]
Trastuzumab	DMZQOUX	Breast cancer	2C60-2C65	Approved	[13]
Tucatinib	DMBESUA	HER2-positive breast cancer	2C60-2C65	Approved	[14]
Pertuzumab	DMHJV0X	Adrenal gland neoplasm		Approved	[15]
Masoprocol	DMMVNZ0	Prostate cancer	2C82.0	Approved	[16]

Drug(s) Targeting Epidermal growth factor receptor (EGFR)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[17]
Lapatinib	DM3BH1Y	Breast cancer	2C60-2C65	Approved	[7]
Gefitinib	DM15F0X	Colon adenocarcinoma		Approved	[18]
Erlotinib	DMCMBHA	Adrenal gland neoplasm		Approved	[19]
Vandetanib	DMRICNP	Solid tumour/cancer	2A00-2F9Z	Approved	[4]
Dacomitinib	DMOH8VY	Non-small-cell lung cancer	2C25.Y	Approved	[20]
BIBW 2992	DMTKD7Q	Non-small-cell lung cancer	2C25.Y	Approved	[9]
SKI-758	DMQ8E9R	Ischemia	8B10-8B11	Approved	[21]
Epidermal growth factor	DMVONE6	Vulnerary	ND56.Z	Approved	[20]
Merimepodib	DM0HS92	Breast cancer	2C60-2C65	Approved	[10]

Drug(s) Targeting Vascular endothelial growth factor receptor 2 (KDR)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[22]
Romiplostim	DM3U7SZ	Thrombocytopenia	3B64	Approved	[23]
Regorafenib	DMHSY1I	Gastrointestinal stromal tumour	2B5B	Approved	[24]
Sunitinib	DMCBJSR	Acute undifferentiated leukemia		Approved	[25]
Axitinib	DMGVH6N	Renal cell carcinoma	2C90	Approved	[26]
Vandetanib	DMRICNP	Solid tumour/cancer	2A00-2F9Z	Approved	[4]
Pazopanib HCl	DM6U9CQ	Renal cell carcinoma	2C90	Approved	[27]
Fruquintinib	DMHOSCQ	Colorectal cancer	2B91.Z	Approved	[28]
Cabozantinib	DMIYDT4	Medullary thyroid gland carcinoma		Approved	[29]
Tivozanib	DMUKC5L	Renal cell carcinoma	2C90	Approved	[30]

Drug(s) Targeting ERBB2 messenger RNA (HER2 mRNA)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-690514	DMX302C	Chronic pain	MG30	Phase 2	[31]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[32]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[32]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[32]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[33]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[32]
PMID24915291C38	DMBXT9J	Discovery agent	N.A.	Investigative	[34]
Geldanamycin-estradiol hybrid	DMUSJ96	Discovery agent	N.A.	Investigative	[35]
CL-387785	DMLKFZC	Discovery agent	N.A.	Investigative	[36]
HDS-029	DMLRUVA	Discovery agent	N.A.	Investigative	[36]

Drug(s) Metabolized By Cytochrome P450 3A4 (CYP3A4)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[37]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[38]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[39]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[40]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[41]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[42]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[43]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[44]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[38]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[45]

Drug(s) Affected By Bile salt export pump (ABCB11)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Glimepiride	DM5FSJA	Diabetic complication	5A2Y	Approved	[46]
Ezetimibe	DM7A8TW	Atherosclerosis	BD40	Approved	[47]
Glipizide	DMZA5PQ	Diabetic complication	5A2Y	Approved	[47]
Bosentan	DMIOGBU	Pulmonary arterial hypertension	BB01.0	Approved	[48]
Indinavir	DM0T3YH	Human immunodeficiency virus infection	1C62	Approved	[46]
Ofloxacin	DM0VQN3	Acute gonococcal cervicitis		Approved	[47]
Primidone	DM0WX6I	Epilepsy	8A60-8A68	Approved	[49]
Gefitinib	DM15F0X	Colon adenocarcinoma		Approved	[46]
Drospirenone	DM1A9W3	Acne vulgaris	ED80	Approved	[6]
Nitrendipine	DM21C09	Hypertension	BA00-BA04	Approved	[46]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[2]
ERBB2 messenger RNA (HER2 mRNA)	TTR5TV4	ERBB2_HUMAN	Inhibitor	[3]
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[4]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[2]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[5]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Gene/Protein Processing	[6]

References

• [1] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021154)
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [7] Triple negative breast cancer--current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009 Mar;153(1):13-7.
• [8] 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: 7422).
• [9] Boehringer Ingelheim. Product Development Pipeline. June 2 2009.
• [10] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [11] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [13] Her2/neu is not a commonly expressed therapeutic target in melanoma -- a large cohort tissue microarray study. Melanoma Res. 2004 Jun;14(3):207-10.
• [14] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [15] Clinical pipeline report, company report or official report of Roche (2009).
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [17] Nasopharyngeal carcinoma: Current treatment options and future directions. J Nasopharyng Carcinoma, 2014, 1(16): e16.
• [18] Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. Br J Cancer. 2004 Feb 9;90(3):566-72.
• [19] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [20] 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. (Target id: 1797).
• [21] Synthesis and Src kinase inhibitory activity of a series of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-furyl-3-quinolinecarbonitriles. J Med Chem. 2006 Dec 28;49(26):7868-76.
• [22] Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther.2008 Oct;7(10):3129-40.
• [23] Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem. 2002 Dec 19;45(26):5687-93.
• [24] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [25] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [26] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [27] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [28] Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45.
• [29] Clinical pipeline report, company report or official report of Exelixis (2011).
• [30] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services
• [31] Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2. J Pharm Sci. 2010 Aug;99(8):3579-93.
• [32] Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81.
• [33] Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitum... J Med Chem. 2005 Sep 8;48(18):5639-43.
• [34] Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity. J Med Chem. 2014 Jun 26;57(12):5112-28.
• [35] Synthesis and evaluation of geldanamycin-estradiol hybrids. Bioorg Med Chem Lett. 1999 May 3;9(9):1233-8.
• [36] Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB... J Med Chem. 2006 Feb 23;49(4):1475-85.
• [37] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [38] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [39] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [40] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [41] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [42] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [43] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [44] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [45] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [46] 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.
• [47] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [48] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [49] 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.