Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTR5TV4)

• DTT Name: ERBB2 messenger RNA (HER2 mRNA)
• Synonyms: Tyrosine kinase-type cell surface receptor HER2 (mRNA); Tyrosine kinase receptor ErbB2 (mRNA); Receptor tyrosine-protein kinase erbB-2 (mRNA); Proto-oncogene c-ErbB-2 (mRNA); Proto-oncogene Neu (mRNA); P185erbB2 (mRNA); NGL (mRNA); NEU proto-oncogene (mRNA); NEU (mRNA); Metastatic lymph node gene 19 protein (mRNA); MLN19 (mRNA); MLN 19 (mRNA); HER2/neu (mRNA); HER2 (erbB2/neu) (mRNA); HER-2 (mRNA); Erb2 (mRNA); Epidermal growth factor receptor 2 (mRNA); CD340 (mRNA); C-erbB-2 oncoprotein (mRNA); C-erbB-2 (mRNA)
• Gene Name: ERBB2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: ERBB2_HUMAN
• TTD ID: T96788
• EC Number: EC 2.7.10.1
• Sequence:
  MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL
  ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG
  DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA
  LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC
  AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP
  YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN
  IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP
  DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV
  PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC
  VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC
  PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG
  ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL
  RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP
  YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR
  LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT
  HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM
  IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA
  EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG
  AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV
  NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ
  GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV
• Function: Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
• KEGG Pathway:
  ErbB signaling pathway (hsa04012)
  Calcium signaling pathway (hsa04020)
  HIF-1 signaling pathway (hsa04066)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Prostate cancer (hsa05215)
  Bladder cancer (hsa05219)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  PLCG1 events in ERBB2 signaling (R-HSA-1251932)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GRB2 events in ERBB2 signaling (R-HSA-1963640)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  RAF/MAP kinase cascade (R-HSA-5673001)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HKI-272	DM6QOVN	Breast cancer	2C60-2C65	Phase 3	[1]
BMS-690514	DMX302C	Chronic pain	MG30	Phase 2	[2]

26 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(1-Benzyl-1H-indol-5-yl)-quinazolin-4-yl-amine	DM0SCW9	Discovery agent	N.A.	Investigative	[3]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[4]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[4]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[4]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[4]
4-(3-phenoxylphenyl)-5-cyano-2H-1,2,3-triazole	DMSXG23	Discovery agent	N.A.	Investigative	[5]
4-(4-bromophenyl)-5-cyano-2H-1,2,3-triazole	DMFEBCO	Discovery agent	N.A.	Investigative	[5]
4-(4-chlorophenyl)-5-cyano-2H-1,2,3-triazole	DMVN7GC	Discovery agent	N.A.	Investigative	[5]
4-(4-isopropylphenyl)-5-cyano-2H-1,2,3-triazole	DMRGM21	Discovery agent	N.A.	Investigative	[5]
4-(Bis(2-chloroethyl)amino)-N-p-tolylbenzamide	DMNE5H7	Discovery agent	N.A.	Investigative	[6]
4557W	DMLE0I7	Discovery agent	N.A.	Investigative	[3]
AG-213	DMT3ML6	Discovery agent	N.A.	Investigative	[7]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[8]
CL-387785	DMLKFZC	Discovery agent	N.A.	Investigative	[9]
Geldanamycin-estradiol hybrid	DMUSJ96	Discovery agent	N.A.	Investigative	[10]
HDS-029	DMLRUVA	Discovery agent	N.A.	Investigative	[9]
ISIS 12882	DMAXB8T	Discovery agent	N.A.	Investigative	[11]
ISIS 12883	DMND0JL	Discovery agent	N.A.	Investigative	[11]
ISIS 12884	DMS15A3	Discovery agent	N.A.	Investigative	[11]
ISIS 9002	DMLIRKY	Discovery agent	N.A.	Investigative	[11]
ISIS 9003	DMBL2CG	Discovery agent	N.A.	Investigative	[11]
ISIS 9005	DM3PVGC	Discovery agent	N.A.	Investigative	[11]
N-(4-m-Tolylamino-quinazolin-6-yl)-acrylamide	DMEBGF1	Discovery agent	N.A.	Investigative	[12]
PD-168393	DMN8M5P	Discovery agent	N.A.	Investigative	[12]
PMID24915291C38	DMBXT9J	Discovery agent	N.A.	Investigative	[13]
PNT-500	DMIEKVB	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	3.50E-77	0.49	1.12
Rectal cancer	2C82	Rectal colon tissue	9.58E-01	-0.12	-0.23
Prostate cancer	2C82	Prostate	3.64E-01	-0.23	-0.38
Lung cancer	2C82	Lung tissue	7.14E-04	-0.13	-0.19

References

• [1] 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.
• [2] 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.
• [3] Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2. Bioorg Med Chem Lett. 2001 Jun 4;11(11):1401-5.
• [4] Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81.
• [5] Synthesis and biological evaluation of 4-aryl-5-cyano-2H-1,2,3-triazoles as inhibitor of HER2 tyrosine kinase. Bioorg Med Chem. 2007 Feb 1;15(3):1533-8.
• [6] Synthesis, biological evaluation and molecular docking studies of amide-coupled benzoic nitrogen mustard derivatives as potential antitumor agents. Bioorg Med Chem. 2010 Jan 15;18(2):880-6.
• [7] Syntheses of 4-(indole-3-yl)quinazolines: a new class of epidermal growth factor receptor tyrosine kinase inhibitors. Eur J Med Chem. 2008 Jul;43(7):1478-88.
• [8] 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.
• [9] 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.
• [10] Synthesis and evaluation of geldanamycin-estradiol hybrids. Bioorg Med Chem Lett. 1999 May 3;9(9):1233-8.
• [11] US patent application no. 5,968,748, Antisense oligonucleotide modulation of human HER-2 expression.
• [12] Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP... J Med Chem. 1999 May 20;42(10):1803-15.
• [13] 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.
• [14] 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: 2019).