Target Information
Target General Information | Top | |||||
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Target ID |
T82105
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Target Name |
Biliary glycoprotein 1 (CEACAM1)
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Synonyms |
Biliary glycoprotein 1; BGP-1; DE AltName: CD_antigen=CD66a
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Gene Name |
CEACAM1
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (By similarity). Plays a role as coinhibitory receptor in immune response, insulin action and functions also as an activator during angiogenesis. Its coinhibitory receptor function is phosphorylation- and PTPN6 -dependent, which in turn, suppress signal transduction of associated receptors by dephosphorylation of their downstream effectors. Plays a role in immune response, of T cells, natural killer (NK) and neutrophils. Upon TCR/CD3 complex stimulation, inhibits TCR-mediated cytotoxicity by blocking granule exocytosis by mediating homophilic binding to adjacent cells, allowing interaction with and phosphorylation by LCK and interaction with the TCR/CD3 complex which recruits PTPN6 resulting in dephosphorylation of CD247 and ZAP70. Also inhibits T cell proliferation and cytokine production through inhibition of JNK cascade and plays a crucial role in regulating autoimmunity and anti-tumor immunity by inhibiting T cell through its interaction with HAVCR2. Upon natural killer (NK) cells activation, inhibit KLRK1-mediated cytolysis of CEACAM1-bearing tumor cells by trans-homophilic interactions with CEACAM1 on the target cell and lead to cis-interaction between CEACAM1 and KLRK1, allowing PTPN6 recruitment and then VAV1 dephosphorylation. Upon neutrophils activation negatively regulates IL1B production by recruiting PTPN6 to a SYK-TLR4-CEACAM1 complex, that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome. Downregulates neutrophil production by acting as a coinhibitory receptor for CSF3R by downregulating the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (By similarity). Also regulates insulin action by promoting INS clearance and regulating lipogenesis in liver through regulating insulin signaling (By similarity). Upon INS stimulation, undergoes phosphorylation by INSR leading to INS clearance by increasing receptor-mediated insulin endocytosis. This inernalization promotes interaction with FASN leading to receptor-mediated insulin degradation and to reduction of FASN activity leading to negative regulation of fatty acid synthesis. INSR-mediated phosphorylation also provokes a down-regulation of cell proliferation through SHC1 interaction resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 and phosphatidylinositol 3-kinase pathways (By similarity). Functions as activator in angiogenesis by promoting blood vessel remodeling through endothelial cell differentiation and migration and in arteriogenesis by increasing the number of collateral arteries and collateral vessel calibers after ischemia. Also regulates vascular permeability through the VEGFR2 signaling pathway resulting in control of nitric oxide production (By similarity). Downregulates cell growth in response to EGF through its interaction with SHC1 that mediates interaction with EGFR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity). Negatively regulates platelet aggregation by decreasing platelet adhesion on type I collagen through the GPVI-FcRgamma complex (By similarity). Inhibits cell migration and cell scattering through interaction with FLNA; interfers with the interaction of FLNA with RALA. Mediates bile acid transport activity in a phosphorylation dependent manner (By similarity). Negatively regulates osteoclastogenesis (By similarity).
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UniProt ID | ||||||
Sequence |
MGHLSAPLHRVRVPWQGLLLTASLLTFWNPPTTAQLTTESMPFNVAEGKEVLLLVHNLPQ
QLFGYSWYKGERVDGNRQIVGYAIGTQQATPGPANSGRETIYPNASLLIQNVTQNDTGFY TLQVIKSDLVNEEATGQFHVYPELPKPSISSNNSNPVEDKDAVAFTCEPETQDTTYLWWI NNQSLPVSPRLQLSNGNRTLTLLSVTRNDTGPYECEIQNPVSANRSDPVTLNVTYGPDTP TISPSDTYYRPGANLSLSCYAASNPPAQYSWLINGTFQQSTQELFIPNITVNNSGSYTCH ANNSVTGCNRTTVKTIIVTELSPVVAKPQIKASKTTVTGDKDSVNLTCSTNDTGISIRWF FKNQSLPSSERMKLSQGNTTLSINPVKREDAGTYWCEVFNPISKNQSDPIMLNVNYNALP QENGLSPGAIAGIVIGVVALVALIAVALACFLHFGKTGRASDQRDLTEHKPSVSNHTQDH SNDPPNKMNEVTYSTLNFEAQQPTQPTSASPSLTATEIIYSEVKKQ Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | CM24 | Drug Info | Phase 1/2 | Aggressive cancer | [2] | |
2 | NEO-201 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 1 Inhibitor drugs | + | ||||
1 | NEO-201 | Drug Info | [1] |
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: B-Octylglucoside | Ligand Info | |||||
Structure Description | Crystal structure of E99A mutant of human CEACAM1 | PDB:6XNO | ||||
Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [5] |
PDB Sequence |
QLTTESMPFN
10 VAEGKEVLLL20 VHNLPQQLFG30 YSWYKGERVD40 GNRQIVGYAI50 GTQQATPGPA 60 NSGRETIYPN70 ASLLIQNVTQ80 NDTGFYTLQV90 IKSDLVNEAA100 TGQFHVY |
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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 Tissue Distribution
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 1.86E-05 |
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Closeness centrality | 2.28E-01 | Radiality | 1.40E+01 | Clustering coefficient | 3.33E-01 |
Neighborhood connectivity | 9.97E+01 | Topological coefficient | 3.60E-01 | Eccentricity | 12 |
Download | Click to Download the Full PPI Network of This Target | ||||
References | Top | |||||
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REF 1 | The Monoclonal Antibody NEO-201 Enhances Natural Killer Cell Cytotoxicity Against Tumor Cells Through Blockade of the Inhibitory CEACAM5/CEACAM1 Immune Checkpoint Pathway. Cancer Biother Radiopharm. 2020 Apr;35(3):190-198. | |||||
REF 2 | ClinicalTrials.gov (NCT04731467) A Phase 1/2 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of CM24 in Combination With Nivolumab in Adults With Advanced Solid Tumors. U.S.National Institutes of Health. | |||||
REF 3 | ClinicalTrials.gov (NCT03476681) QUILT-3.017: Study of NEO-201 in Solid Tumors. U.S. National Institutes of Health. | |||||
REF 4 | Clinical pipeline report, company report or official report of Purple | |||||
REF 5 | Structural basis of the dynamic human CEACAM1 monomer-dimer equilibrium. Commun Biol. 2021 Mar 19;4(1):360. |
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