Target Information
| Target General Information | Top | |||||
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| Target ID |
T15855
(Former ID: TTDI03156)
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| Target Name |
Dipeptidyl peptidase 8 (DPP-8)
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| Synonyms |
Prolyl dipeptidase DPP8; MSTP141; MSTP135; MSTP097; Dipeptidyl peptidase VIII; Dipeptidyl peptidase IV-related protein 1; DPRP1; DPRP-1; DPP VIII; DP8
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| Gene Name |
DPP8
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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 |
Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.14.5
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| Sequence |
MWKRSEQMKIKSGKCNMAAAMETEQLGVEIFETADCEENIESQDRPKLEPFYVERYSWSQ
LKKLLADTRKYHGYMMAKAPHDFMFVKRNDPDGPHSDRIYYLAMSGENRENTLFYSEIPK TINRAAVLMLSWKPLLDLFQATLDYGMYSREEELLRERKRIGTVGIASYDYHQGSGTFLF QAGSGIYHVKDGGPQGFTQQPLRPNLVETSCPNIRMDPKLCPADPDWIAFIHSNDIWISN IVTREERRLTYVHNELANMEEDARSAGVATFVLQEEFDRYSGYWWCPKAETTPSGGKILR ILYEENDESEVEIIHVTSPMLETRRADSFRYPKTGTANPKVTFKMSEIMIDAEGRIIDVI DKELIQPFEILFEGVEYIARAGWTPEGKYAWSILLDRSQTRLQIVLISPELFIPVEDDVM ERQRLIESVPDSVTPLIIYEETTDIWINIHDIFHVFPQSHEEEIEFIFASECKTGFRHLY KITSILKESKYKRSSGGLPAPSDFKCPIKEEIAITSGEWEVLGRHGSNIQVDEVRRLVYF EGTKDSPLEHHLYVVSYVNPGEVTRLTDRGYSHSCCISQHCDFFISKYSNQKNPHCVSLY KLSSPEDDPTCKTKEFWATILDSAGPLPDYTPPEIFSFESTTGFTLYGMLYKPHDLQPGK KYPTVLFIYGGPQVQLVNNRFKGVKYFRLNTLASLGYVVVVIDNRGSCHRGLKFEGAFKY KMGQIEIDDQVEGLQYLASRYDFIDLDRVGIHGWSYGGYLSLMALMQRSDIFRVAIAGAP VTLWIFYDTGYTERYMGHPDQNEQGYYLGSVAMQAEKFPSEPNRLLLLHGFLDENVHFAH TSILLSFLVRAGKPYDLQIYPQERHSIRVPESGEHYELHLLHYLQENLGSRIAALKVI 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) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Talabostat | Drug Info | Phase 3 | Constitutional neutropenia | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | Talabostat | Drug Info | [1] | |||
| 2 | Thiomorpholine derivative 1 | Drug Info | [4] | |||
| 3 | Thiomorpholine derivative 2 | Drug Info | [4] | |||
| 4 | 1G244 | Drug Info | [5] | |||
| 5 | PMID15664838C18 | Drug Info | [6] | |||
| 6 | PMID20684603C24dd | Drug Info | [7] | |||
| 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: S,S-(2-Hydroxyethyl)Thiocysteine | Ligand Info | |||||
| Structure Description | DPP8 - SLRFLYEG, space group 20 | PDB:6EOP | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [8] |
| PDB Sequence |
LEPFYVERYS
57 WSQLKKLLAD67 TRKYHGYMMA77 KAPHDFMFVK87 RNDPDGPHSD97 RIYYLAMSNR 109 ENTLFYSEIP119 KTINRAAVLM129 LSWKPLLDLF139 QYSREEELLR156 ERKRIGTVGI 166 ASYDYHQGSG176 TFLFQAGSGI186 YHVKDGGPQG196 FTQQPLRPNL206 VETSCPNIRM 216 DPKLCPADPD226 WIAFIHSNDI236 WISNIVTREE246 RRLTYVHNEL256 ANMEEDARSA 266 GVATFVLQEE276 FDRYSGYWWC286 PKAETTPSGG296 KILRILYEEN306 DESEVEIIHV 316 TSPMLETRRA326 DSFRYPKTGT336 ANPKVTFKMS346 EIMIDAEGRI356 IDVIDKELIQ 366 PFEILFEGVE376 YIARAGWTPE386 GKYAWSILLD396 RSQTRLQIVL406 ISPELFIPVE 416 DDVMERQRLI426 ESVPDSVTPL436 IIYEETTDIW446 INIHDIFHVF456 PQSHEEEIEF 466 IFASECKTGF476 RHLYKITSIL486 KESKYKRSSG496 GLPAPSDFKC506 PIKEEIAITS 516 GEWEVLGRHG526 SNIQVDEVRR536 LVYFEGTKDS546 PLEHHLYVVS556 YVNPGEVTRL 566 TDRGYSHSCC576 ISQHCDFFIS586 KYSNQKNPHC596 VSLYKLSSPE606 DDPTCKTKEF 616 WATILDSAGP626 LPDYTPPEIF636 SFESTTGFTL646 YGMLYKPHDL656 QPGKKYPTVL 666 FIYGGPQVQL676 VNNRFKGVKY686 FRLNTLASLG696 YVVVVIDNRG706 SHRGLKFEGA 717 FKYKMGQIEI727 DDQVEGLQYL737 ASRYDFIDLD747 RVGIHGWSYG757 GYLSLMALMQ 767 RSDIFRVAIA777 GAPVTLWIFY787 DTGYTERYMG797 HPDQNEQGYY807 LGSVAMQAEK 817 FPSEPNRLLL827 LHGFLDENVH837 FAHTSILLSF847 LVRAGKPYDL857 QIYPQERHSI 867 RVPESGEHYE877 LHLLHYLQEN887 LGSRIAALKV897
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| Ligand Name: 1G244 | Ligand Info | |||||
| Structure Description | Crystal structure of DPP8 in complex with 1G244 | PDB:6TRX | ||||
| Method | X-ray diffraction | Resolution | 3.20 Å | Mutation | No | [9] |
| PDB Sequence |
LEPFYVERYS
57 WSQLKKLLAD67 TRKYHGYMMA77 KAPHDFMFVK87 RNDPDGPHSD97 RIYYLAMSNR 109 ENTLFYSEIP119 KTINRAAVLM129 LSWKPLLDLY148 SREEELLRER158 KRIGTVGIAS 168 YDYHQGSGTF178 LFQAGSGIYH188 VKDGGPQGFT198 QQPLRPNLVE208 TSCPNIRMDP 218 KLCPADPDWI228 AFIHSNDIWI238 SNIVTREERR248 LTYVHNELAN258 MEEDARSAGV 268 ATFVLQEEFD278 RYSGYWWCPK288 AETTPSGGKI298 LRILYEENDE308 SEVEIIHVTS 318 PMLETRRADS328 FRYPKTGTAN338 PKVTFKMSEI348 MIDAEGRIID358 VIDKELIQPF 368 EILFEGVEYI378 ARAGWTPEGK388 YAWSILLDRS398 QTRLQIVLIS408 PELFIPVEDD 418 VMERQRLIES428 VPDSVTPLII438 YEETTDIWIN448 IHDIFHVFPQ458 SHEEEIEFIF 468 ASECKTGFRH478 LYKITSILKE488 SKYKRSSGGL498 PAPSDFKCPI508 KEEIAITSGE 518 WEVLGRHGSN528 IQVDEVRRLV538 YFEGTKDSPL548 EHHLYVVSYV558 NPGEVTRLTD 568 RGYSHSCCIS578 QHCDFFISKY588 SNQKNPHCVS598 LYKLSSPEDD608 PTCKTKEFWA 618 TILDSAGPLP628 DYTPPEIFSF638 ESTTGFTLYG648 MLYKPHDLQP658 GKKYPTVLFI 668 YGGPQVQLVN678 NRFKGVKYFR688 LNTLASLGYV698 VVVIDNRGSC708 HRGLKFEGAF 718 KYKMGQIEID728 DQVEGLQYLA738 SRYDFIDLDR748 VGIHGWSYGG758 YLSLMALMQR 768 SDIFRVAIAG778 APVTLWIFYD788 TGYTERYMGH798 PDQNEQGYYL808 GSVAMQAEKF 818 PSEPNRLLLL828 HGFLDENVHF838 AHTSILLSFL848 VRAGKPYDLQ858 IYPQERHSIR 868 VPESGEHYEL878 HLLHYLQENL888 GSRIAALKV
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ARG160
2.918
GLU275
2.994
GLU276
2.759
HIS525
3.503
TYR669
3.324
PRO672
4.183
GLN673
3.260
VAL674
3.759
LEU676
3.489
TYR686
3.574
SER755
3.337
TYR756
3.356
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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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Neuroligin-2 (NLGN2) | 30.075 (40/133) | 3.00E-03 |
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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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| 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 | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | 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 3 | ClinicalTrials.gov (NCT03910660) Phase 1b/2 Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl Peptidases, Administered in Combination With the Anti-Programmed Cell Death 1 Monoclonal Antibody Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype. U.S.National Institutes of Health. | |||||
| REF 4 | DPP-4 inhibitors: a patent review (2012 - 2014).Expert Opin Ther Pat. 2015 Feb;25(2):209-36. | |||||
| REF 5 | Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor. Biochem Pharmacol. 2009 Jul 15;78(2):203-10. | |||||
| REF 6 | Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8. Bioorg Med Chem Lett. 2005 Feb 1;15(3):687-91. | |||||
| REF 7 | Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors. J Med Chem. 2010 Aug 12;53(15):5620-8. | |||||
| REF 8 | Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1437-E1445. | |||||
| REF 9 | Aerosol-based ligand soaking of reservoir-free protein crystals. J Appl Crystallogr. 2021 May 28;54(Pt 3):895-902. | |||||
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