Target Information
| Target General Information | Top | |||||
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| Target ID |
T66252
(Former ID: TTDI03157)
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| Target Name |
Dipeptidyl peptidase 9 (DPP-9)
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| Synonyms |
Dipeptidyl peptidase-like protein 9; Dipeptidyl peptidase IX; Dipeptidyl peptidase IV-related protein 2; DPRP2; DPRP-2; DPP IX; DPLP9; DP9
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| Gene Name |
DPP9
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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 |
MATTGTPTADRGDAAATDDPAARFQVQKHSWDGLRSIIHGSRKYSGLIVNKAPHDFQFVQ
KTDESGPHSHRLYYLGMPYGSRENSLLYSEIPKKVRKEALLLLSWKQMLDHFQATPHHGV YSREEELLRERKRLGVFGITSYDFHSESGLFLFQASNSLFHCRDGGKNGFMVSPMKPLEI KTQCSGPRMDPKICPADPAFFSFINNSDLWVANIETGEERRLTFCHQGLSNVLDDPKSAG VATFVIQEEFDRFTGYWWCPTASWEGSEGLKTLRILYEEVDESEVEVIHVPSPALEERKT DSYRYPRTGSKNPKIALKLAEFQTDSQGKIVSTQEKELVQPFSSLFPKVEYIARAGWTRD GKYAWAMFLDRPQQWLQLVLLPPALFIPSTENEEQRLASARAVPRNVQPYVVYEEVTNVW INVHDIFYPFPQSEGEDELCFLRANECKTGFCHLYKVTAVLKSQGYDWSEPFSPGEDEFK CPIKEEIALTSGEWEVLARHGSKIWVNEETKLVYFQGTKDTPLEHHLYVVSYEAAGEIVR LTTPGFSHSCSMSQNFDMFVSHYSSVSTPPCVHVYKLSGPDDDPLHKQPRFWASMMEAAS CPPDYVPPEIFHFHTRSDVRLYGMIYKPHALQPGKKHPTVLFVYGGPQVQLVNNSFKGIK YLRLNTLASLGYAVVVIDGRGSCQRGLRFEGALKNQMGQVEIEDQVEGLQFVAEKYGFID LSRVAIHGWSYGGFLSLMGLIHKPQVFKVAIAGAPVTVWMAYDTGYTERYMDVPENNQHG YEAGSVALHVEKLPNEPNRLLILHGFLDENVHFFHTNFLVSQLIRAGKPYQLQIYPNERH SIRCPESGEHYEVTLLHFLQEYL 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) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Talabostat | Drug Info | Phase 3 | Constitutional neutropenia | [2] | |
| 2 | BXCL701 | Drug Info | Phase 1/2 | Prostate cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | Talabostat | Drug Info | [1] | |||
| 2 | BXCL701 | Drug Info | [4] | |||
| 3 | Thiomorpholine derivative 1 | Drug Info | [5] | |||
| 4 | Thiomorpholine derivative 2 | Drug Info | [5] | |||
| 5 | 1G244 | 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: 1G244 | Ligand Info | |||||
| Structure Description | DPP9 - 1G244 | PDB:6EOR | ||||
| Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | No | [8] |
| PDB Sequence |
AARFQVQKHS
30 WDGLRSIIHG40 SRKAPHDFQF58 VQKSGPHSHR71 LYYLGMPYRE83 NSLLYSEIPK 93 LLLSWKQMLD110 HFQATPHHGV120 YSREEELLRE130 RKRLGVFGIT140 SYDFHSESGL 150 FLFQASNSLF160 HCRDGGKNGF170 MVSPMKPLEI180 KTQCSGPRMD190 PKICPADPAF 200 FSFINNSDLW210 VANIETGEER220 RLTFCHQNVL233 DDPKSAGVAT243 FVIQEEFDRF 253 TGYWWCPTAS263 WEGLKTLRIL276 YEEVDESEVE286 VIHVPSPALE296 ERKTDSYRYP 306 RTGSKNPKIA316 LKLAEFQTDS326 QGKIVSTQEK336 ELVQPFSSLF346 PKVEYIARAG 356 WTRDGKYAWA366 MFLDRPQQWL376 QLVLLPPALF386 IPSTENEEQR396 LASARAVPRN 406 VQPYVVYEEV416 TNVWINVHDI426 FYPFPQLCFL442 RANECKTGFC452 HLYKVTAVLK 462 SQGYDWSEPF472 SPGEDEFKCP482 IKEEIALTSG492 EWEVLARHGS502 KIWVNEETKL 512 VYFQGTKDTP522 LEHHLYVVSY532 EAAGEIVRLT542 TPGFSHSCSM552 SQNFDMFVSH 562 YSSVSTPPCV572 HVYKLSGPDD582 DPLHKQPRFW592 ASMMEADYVP607 PEIFHFHTRS 617 DVRLYGMIYK627 PHALQPGKKH637 PTVLFVYGGP647 QVQLVNNSFK657 GIKYLRLNTL 667 ASLGYAVVVI677 DGRGSCQRGL687 RFEGALKNQM697 GQVEIEDQVE707 GLQFVAEKYG 717 FIDLSRVAIH727 GWSYGGFLSL737 MGLIHKPQVF747 KVAIAGAPVT757 VWMAYDTGYT 767 ERYMDVPENN777 QHGYEAGSVA787 LHVEKLPNEP797 NRLLILHGFL807 DENVHFFHTN 817 FLVSQLIRAG827 KPYQLQIYPN837 ERHSIRCPES847 GEHYEVTLLH857 FLQEYLHH |
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ARG133
2.808
GLU248
2.320
GLU249
2.545
HIS500
4.160
TYR644
3.150
PRO647
4.147
GLN648
3.662
VAL649
4.146
LYS660
3.798
SER730
3.026
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| Ligand Name: Cysteine Sulfenic Acid | Ligand Info | |||||
| Structure Description | Crystal structure of DPP9 in complex with a 4-oxo-b-lactam based inhibitor, A295 | PDB:7ZXS | ||||
| Method | X-ray diffraction | Resolution | 1.81 Å | Mutation | No | [9] |
| PDB Sequence |
ARFQVQKHSW
31 DGLRSIIHGS41 RKYSGLIVNK51 APHDFQFVQK61 TDESGPHSHR71 LYYLGMPYGS 81 RENSLLYSEI91 PKKVRKEALL101 LLSWKQMLDH111 FQATPHHGVY121 SREEELLRER 131 KRLGVFGITS141 YDFHSESGLF151 LFQASNSLFH161 CRDGGKNGFM171 VSPMKPLEIK 181 TQCSGPRMDP191 KICPADPAFF201 SFINNSDLWV211 ANIETGEERR221 LTFCHQGLSN 231 VLDDPKSAGV241 ATFVIQEEFD251 RFTGYWWCPT261 ASWEGSEGLK271 TLRILYEEVD 281 ESEVEVIHVP291 SPALEERKTD301 SYRYPRTGSK311 NPKIALKLAE321 FQTDSQGKIV 331 STQEKELVQP341 FSSLFPKVEY351 IARAGWTRDG361 KYAWAMFLDR371 PQQWLQLVLL 381 PPALFIPSTE391 NEEQRLASAR401 AVPRNVQPYV411 VYEEVTNVWI421 NVHDIFYPFP 431 QSEGEDELCF441 LRANECKTGF451 CHLYKVTAVL461 KSQGYDWSEP471 FSPGEDEFKC 481 PIKEEIALTS491 GEWEVLARHG501 SKIWVNEETK511 LVYFQGTKDT521 PLEHHLYVVS 531 YEAAGEIVRL541 TTPGFSHSCS551 MSQNFDMFVS561 HYSSVSTPPC571 VHVYKLSGPD 581 DDPLHKQPRF591 WASMMEAASC601 PPDYVPPEIF611 HFHTRSDVRL621 YGMIYKPHAL 631 QPGKKHPTVL641 FVYGGPQVQL651 VNNSFKGIKY661 LRLNTLASLG671 YAVVVIDGRG 681 SCQRGLRFEG691 ALKNQMGQVE701 IEDQVEGLQF711 VAEKYGFIDL721 SRVAIHGWSY 731 GGFLSLMGLI741 HKPQVFKVAI751 AGAPVTVWMA761 YDTGYTERYM771 DVPENNQHGY 781 EAGSVALHVE791 KLPNEPNRLL801 ILHGFLDENV811 HFFHTNFLVS821 QLIRAGKPYQ 831 LQIYPNERHS841 IRPESGEHYE852 VTLLHFLQEY862 LHH
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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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| 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 inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma. J Immunother Cancer. 2021 Nov;9(11):e002837. | |||||
| REF 5 | DPP-4 inhibitors: a patent review (2012 - 2014).Expert Opin Ther Pat. 2015 Feb;25(2):209-36. | |||||
| REF 6 | Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor. Biochem Pharmacol. 2009 Jul 15;78(2):203-10. | |||||
| 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 | Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9. Angew Chem Int Ed Engl. 2022 Nov 21;61(47):e202210498. | |||||
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