Target Information
| Target General Information | Top | |||||
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| Target ID |
T92057
(Former ID: TTDC00114)
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| Target Name |
Erbb4 tyrosine kinase receptor (Erbb-4)
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| Synonyms |
Tyrosine kinase-type cell surface receptor HER4; Receptor tyrosine-protein kinase erbB-4; Proto-oncogene-like protein c-ErbB-4; P180erbB4; HER4
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| Gene Name |
ERBB4
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| Function |
Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| Sequence |
MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T05DRQ | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Dacomitinib | Drug Info | Approved | Non-small-cell lung cancer | [2] | |
| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | RG7388 | Drug Info | Phase 3 | Solid tumour/cancer | [3] | |
| 2 | CI-1033 | Drug Info | Phase 2 | Lymphoma | [4], [5] | |
| 3 | JI-101 | Drug Info | Phase 2 | Solid tumour/cancer | [6] | |
| 4 | JNJ-26483327 | Drug Info | Phase 1 | Solid tumour/cancer | [7] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | Dacomitinib | Drug Info | [1] | |||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | RG7388 | Drug Info | [8] | |||
| 2 | CI-1033 | Drug Info | [9], [10] | |||
| 3 | JNJ-26483327 | Drug Info | [12] | |||
| 4 | HDS-029 | Drug Info | [13] | |||
| 5 | PMID24915291C38 | Drug Info | [14] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | JI-101 | Drug Info | [11] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Lapatinib | Ligand Info | |||||
| Structure Description | crystal structure of the ErbB4 kinase in complex with lapatinib | PDB:3BBT | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [15] |
| PDB Sequence |
AQLRILKETE
692 LKRVKVLGSG702 AFGTVYKGIW712 VPEGETVKIP722 VAIKILNEGP734 KANVEFMDEA 744 LIMASMDHPH754 LVRLLGVCLS764 PTIQLVTQLM774 PHGCLLEYVH784 EHKDNIGSQL 794 LLNWCVQIAK804 GMMYLEERRL814 VHRDLAARNV824 LVKSPNHVKI834 TDFGLARLLP 858 IKWMALECIH868 YRKFTHQSDV878 WSYGVTIWEL888 MTFGGKPYDG898 IPTREIPDLL 908 EKGERLPQPP918 ICTIDVYMVM928 VKCWMIDADS938 RPKFKELAAE948 FSRMARDPQR 958 YLVIQDDRMK969 LPSP
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LEU699
4.129
VAL707
3.488
ALA724
3.216
ILE725
3.849
LYS726
3.390
MET747
3.607
VAL756
4.158
ARG757
4.654
LEU758
3.926
LEU769
3.252
VAL770
4.700
THR771
3.494
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| Ligand Name: N-{3-Chloro-4-[(3-Fluorobenzyl)oxy]phenyl}-6-Ethylthieno[3,2-D]pyrimidin-4-Amine | Ligand Info | |||||
| Structure Description | ErbB4 kinase domain complexed with a thienopyrimidine inhibitor | PDB:2R4B | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [16] |
| PDB Sequence |
LVEPLTPSGT
703 APNQAQLRIL713 KETELKRVKV723 LGSGAFGTVY733 KGIWVPEGET743 VKIPVAIKIL 753 NANVEFMDEA769 LIMASMDHPH779 LVRLLGVCLS789 PTIQLVTQLM799 PHGCLLEYVH 809 EHKDNIGSQL819 LLNWCVQIAK829 GMMYLEERRL839 VHRDLAARNV849 LVKSPNHVKI 859 TDFGLARLLE869 GDEKEYNADG879 GKMPIKWMAL889 ECIHYRKFTH899 QSDVWSYGVT 909 IWELMTFGGK919 PYDGIPTREI929 PDLLEKGERL939 PQPPICTIDV949 YMVMVKCWMI 959 DADSRPKFKE969 LAAEFSRMAR979 DPQRYLVIQG989 DD
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LEU724
4.051
VAL732
3.703
ALA749
3.341
ILE750
4.331
LYS751
3.571
MET772
3.844
VAL781
3.587
ARG782
3.505
LEU783
3.238
LEU794
3.195
VAL795
4.142
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| ErbB signaling pathway | hsa04012 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 38 | Degree centrality | 4.08E-03 | Betweenness centrality | 1.90E-03 |
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| Closeness centrality | 2.53E-01 | Radiality | 1.44E+01 | Clustering coefficient | 1.49E-01 |
| Neighborhood connectivity | 4.01E+01 | Topological coefficient | 5.50E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | ErbB signaling pathway | |||||
| 2 | Calcium signaling pathway | |||||
| 3 | Endocytosis | |||||
| 4 | Proteoglycans in cancer | |||||
| Panther Pathway | [+] 3 Panther Pathways | + | ||||
| 1 | Alzheimer disease-presenilin pathway | |||||
| 2 | Cadherin signaling pathway | |||||
| 3 | EGF receptor signaling pathway | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | ErbB Signaling Pathway | |||||
| 2 | EV release from cardiac cells and their functional effects | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 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). | |||||
| REF 2 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 3 | Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.Nat Rev Drug Discov. 2016 Aug;15(8):533-50. | |||||
| REF 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: 5675). | |||||
| REF 5 | Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem. 2000 Apr 6;43(7):1380-97. | |||||
| REF 6 | Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov. 2014 Jan;13(1):39-62. | |||||
| REF 7 | ClinicalTrials.gov (NCT00676299) A Safety and Dose-finding Study of JNJ-26483327, a Drug in Development for Cancer, for Patients With Advanced and/or Refractory Solid Malignancies.. U.S. National Institutes of Health. | |||||
| REF 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. (Target id: 1799). | |||||
| REF 9 | 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. | |||||
| REF 10 | A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4274-82. | |||||
| REF 11 | A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.Invest New Drugs.2015 Dec;33(6):1217-24. | |||||
| REF 12 | National Cancer Institute Drug Dictionary (drug id 596693). | |||||
| REF 13 | 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. | |||||
| REF 14 | 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. | |||||
| REF 15 | Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure. 2008 Mar;16(3):460-7. | |||||
| REF 16 | 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2773-8. | |||||
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