Target Information
| Target General Information | Top | |||||
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| Target ID |
T53764
(Former ID: TTDR01154)
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| Target Name |
Prolyl endopeptidase FAP (FAP)
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| Synonyms |
Integral membrane serine protease; Fibroblast activation protein alpha; FAP; Antiplasmin-cleaving enzyme; APCE; 170-kDa melanoma membrane-bound gelatinase
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| Gene Name |
FAP
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Neutropenia [ICD-11: 4B00] | |||||
| Function |
Cell surface glycoprotein serine protease that participatesin extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble formsexhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2 (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248, PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vibronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Have also dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120, PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416, PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721, PubMed:24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.26
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| Sequence |
MKTWVKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPN
WISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSK LWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQRPGDPP FQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYG DEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLTWVT DERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYD AISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPG RRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGR TDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQV YGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQ ITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVY TERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNA QVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | Talabostat | Drug Info | Phase 3 | Constitutional neutropenia | [1] | |
| 2 | BIBH 1 | Drug Info | Phase 2 | Solid tumour/cancer | [2] | |
| 3 | Sibrotuzumab | Drug Info | Phase 2 | Metastatic colorectal cancer | [3] | |
| 4 | AMG 506 | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
| 5 | NG-641 | Drug Info | Phase 1 | Solid tumour/cancer | [5] | |
| 6 | RG7461 | Drug Info | Phase 1 | Solid tumour/cancer | [6], [7] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | FAP5-DM1 | Drug Info | Preclinical | Solid tumour/cancer | [8] | |
| 2 | PT630 | Drug Info | Preclinical | Lung cancer | [9] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 7 Inhibitor drugs | + | ||||
| 1 | Talabostat | Drug Info | [1] | |||
| 2 | Sibrotuzumab | Drug Info | [10] | |||
| 3 | AMG 506 | Drug Info | [11] | |||
| 4 | PT630 | Drug Info | [9] | |||
| 5 | ARI-3099 | Drug Info | [13] | |||
| 6 | FE-999040 | Drug Info | [14] | |||
| 7 | VA-119930 | Drug Info | [14] | |||
| Antagonist | [+] 2 Antagonist drugs | + | ||||
| 1 | RG7461 | Drug Info | [6] | |||
| 2 | MIP-1231 | Drug Info | [14] | |||
| 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: Linagliptin | Ligand Info | |||||
| Structure Description | Structure of human FAPalpha in complex with linagliptin | PDB:6Y0F | ||||
| Method | X-ray diffraction | Resolution | 2.92 Å | Mutation | No | [15] |
| PDB Sequence |
NTMRALTLKD
46 ILNGTFSYKT56 FFPNWISGQE66 YLHQSADNNI76 VLYNIETGQS86 YTILSNRTMK 96 SVNASNYGLS106 PDRQFVYLES116 DYSKLWRYSY126 TATYYIYDLS136 NGEFVRGNEL 146 PRPIQYLCWS156 PVGSKLAYVY166 QNNIYLKQRP176 GDPPFQITFN186 GRENKIFNGI 196 PDWVYEEEML206 ATKYALWWSP216 NGKFLAYAEF226 NDTDIPVIAY236 SYYGDEQYPR 246 TINIPYPKAG256 AKNPVVRIFI266 IDTTYPAYVG276 PQEVPVPAMI286 ASSDYYFSWL 296 TWVTDERVCL306 QWLKRVQNVS316 VLSICDFRED326 WQTWDCPKTQ336 EHIEESRTGW 346 AGGFFVSTPV356 FSYDAISYYK366 IFSDKDGYKH376 IHYIKDTVEN386 AIQITSGKWE 396 AINIFRVTQD406 SLFYSSNEFE416 EYPGRRNIYR426 ISIGSYPPSK436 KCVTCHLRKE 446 RCQYYTASFS456 DYAKYYALVC466 YGPGIPISTL476 HDGRTDQEIK486 ILEENKELEN 496 ALKNIQLPKE506 EIKKLEVDEI516 TLWYKMILPP526 QFDRSKKYPL536 LIQVYGGPCS 546 QSVRSVFAVN556 WISYLASKEG566 MVIALVDGRG576 TAFQGDKLLY586 AVYRKLGVYE 596 VEDQITAVRK606 FIEMGFIDEK616 RIAIWGWSYG626 GYVSSLALAS636 GTGLFKCGIA 646 VAPVSSWEYY656 ASVYTERFMG666 LPTKDDNLEH676 YKNSTVMARA686 EYFRNVDYLL 696 IHGTADDNVH706 FQNSAQIAKA716 LVNAQVDFQA726 MWYSDQNHGL736 SGLSTNHLYT 746 HMTHFLKQCF756 S
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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 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).
Human Similarity Proteins
Human Tissue Distribution
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There is no similarity protein (E value < 0.005) for this target
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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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| Chemical Structure based Activity Landscape of Target | Top |
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| 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 Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer. Cancer Biol Ther. 2007 Nov;6(11):1691-9. | |||||
| REF 2 | ClinicalTrials.gov (NCT02198274) Intravenous BIBH 1 in Patients With Metastatic Colorectal Cancer. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT02198274) Intravenous BIBH 1 in Patients With Metastatic Colorectal Cancer. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT04049903) Study to Investigate the Safety, Blood Levels and Activity of MP0310 (AMG 506) in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04053283) First in Human Study With NG-641, an Oncolytic Transgene Expressing Adenoviral Vector. U.S. National Institutes of Health. | |||||
| REF 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 7 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 8 | Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res. 2008 Jul 15;14(14):4584-92. | |||||
| REF 9 | Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 2009 Dec;119(12):3613-25. | |||||
| REF 10 | A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003 May;9(5):1639-47. | |||||
| REF 11 | Clinical pipeline report, company report or official report of Amgen. | |||||
| REF 12 | Clinical pipeline report, company report or official report of PsiOxus Therapeutics. | |||||
| REF 13 | Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase. J Med Chem. 2013 May 9;56(9):3467-77. | |||||
| REF 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: 2365). | |||||
| REF 15 | Structure of human FAPalpha in complex with linagliptin | |||||
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