Target Information
Target General Information | Top | |||||
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Target ID |
T27602
(Former ID: TTDS00282)
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Target Name |
Cationic trypsinogen (PRSS1)
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Synonyms |
Trypsin-1; Trypsin I; TRYP1; TRY1; TRP1; Serine protease 1; Beta-trypsin
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Gene Name |
PRSS1
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Mature B-cell lymphoma [ICD-11: 2A85] | |||||
2 | Multiple myeloma [ICD-11: 2A83] | |||||
Function |
Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form against all of these substrates.
Click to Show/Hide
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BioChemical Class |
Peptidase
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UniProt ID | ||||||
EC Number |
EC 3.4.21.4
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Sequence |
MNPLLILTFVAAALAAPFDDDDKIVGGYNCEENSVPYQVSLNSGYHFCGGSLINEQWVVS
AGHCYKSRIQVRLGEHNIEVLEGNEQFINAAKIIRHPQYDRKTLNNDIMLIKLSSRAVIN ARVSTISLPTAPPATGTKCLISGWGNTASSGADYPDELQCLDAPVLSQAKCEASYPGKIT SNMFCVGFLEGGKDSCQGDSGGPVVCNGQLQGVVSWGDGCAQKNKPGVYTKVYNYVKWIK NTIAANS Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T39YFG |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Bortezomib | Drug Info | Approved | Multiple myeloma | [2], [3] | |
Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | Ulinastatin | Drug Info | Phase 3 | Premature labour | [4] | |
2 | Alpha-1 antitrypsin | Drug Info | Phase 2 | Coagulation defect | [5] | |
Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
1 | Dermolastin | Drug Info | Discontinued in Phase 2 | Atopic dermatitis | [6] | |
2 | RWJ-56423 | Drug Info | Discontinued in Phase 1 | Asthma | [7] | |
3 | Patamostat | Drug Info | Terminated | Hypotension | [8] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 31 Inhibitor drugs | + | ||||
1 | Bortezomib | Drug Info | [1] | |||
2 | MELAGATRAN | Drug Info | [9] | |||
3 | Dermolastin | Drug Info | [13], [14], [15], [16] | |||
4 | RWJ-56423 | Drug Info | [17] | |||
5 | BMY-44621 | Drug Info | [18] | |||
6 | 1,3-Di-p-tolyl-[1,3]diazetidine-2,4-dione | Drug Info | [20] | |||
7 | 1,3-Dibenzyl-[1,3]diazetidine-2,4-dione | Drug Info | [20] | |||
8 | 1-(3-Amino-benzyl)-1H-indole-5-carboxamidine | Drug Info | [21] | |||
9 | 1-(3-Nitro-benzyl)-1H-indole-5-carboxamidine | Drug Info | [21] | |||
10 | 1-Benzyl-1H-indole-5-carboxamidine | Drug Info | [21] | |||
11 | 2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine | Drug Info | [22] | |||
12 | 2-(2-Iodo-phenyl)-benzo[d][1,3]oxazin-4-one | Drug Info | [23] | |||
13 | 2-Propionyl-1H-indole-6-carboxamidine | Drug Info | [21] | |||
14 | 4-(3,4-Diethoxy-benzylamino)-benzamidine | Drug Info | [24] | |||
15 | 4-(4-Benzyloxy-3-methoxy-benzylamino)-benzamidine | Drug Info | [24] | |||
16 | 4-(5-Nitro-indol-1-ylmethyl)-benzamidine | Drug Info | [21] | |||
17 | 4-Indol-1-ylmethyl-benzamidine | Drug Info | [21] | |||
18 | 6-Styryl-naphthalene-2-carboxamidine | Drug Info | [25] | |||
19 | 8-Bromo-6-styryl-naphthalene-2-carboxamidine | Drug Info | [25] | |||
20 | 8-Furan-3-yl-6-styryl-naphthalene-2-carboxamidine | Drug Info | [25] | |||
21 | Benzamidine | Drug Info | [27] | |||
22 | CVS-2139 | Drug Info | [28] | |||
23 | CVS-2359 | Drug Info | [28] | |||
24 | GR-133686 | Drug Info | [29] | |||
25 | Grassystatin a | Drug Info | [30] | |||
26 | L-375378 | Drug Info | [31] | |||
27 | Macrocyclic tripeptide motif | Drug Info | [32] | |||
28 | Piperidine-1-carboxamidine | Drug Info | [33] | |||
29 | PMID3514912C9 | Drug Info | [34] | |||
30 | RWJ-50353 | Drug Info | [36] | |||
31 | Tert-butyloxy carbonyl-D-Phe-pro-Arg-H | Drug Info | [37] | |||
Modulator | [+] 7 Modulator drugs | + | ||||
1 | Ulinastatin | Drug Info | [4] | |||
2 | Alpha-1 antitrypsin | Drug Info | [10], [11], [12] | |||
3 | Patamostat | Drug Info | [10], [11], [19] | |||
4 | ATF-HI-8 | Drug Info | [26] | |||
5 | JBP-1 | Drug Info | [10], [11] | |||
6 | POP-1 | Drug Info | [10], [11] | |||
7 | recAAT, PPL Therapeutics/Bayer | Drug Info | [35] |
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 Profiles in Patients | Top | |||||
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Drug Resistance Mutation (DRM) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
1 | Neuroactive ligand-receptor interaction | |||||
2 | Pancreatic secretion | |||||
3 | Protein digestion and absorption | |||||
4 | Influenza A | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | Activation of Matrix Metalloproteinases | |||||
2 | Cobalamin (Cbl, vitamin B12) transport and metabolism | |||||
WikiPathways | [+] 1 WikiPathways | + | ||||
1 | Activation of Matrix Metalloproteinases |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin. J Med Chem. 1995 Apr 28;38(9):1511-22. | |||||
REF 2 | 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: 6391). | |||||
REF 3 | New developments in immunosuppressive therapy for heart transplantation. Expert Opin Emerg Drugs. 2009 Mar;14(1):1-21. | |||||
REF 4 | Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study. Intensive Care Med. 2014 Jun;40(6):830-8. | |||||
REF 5 | Technology evaluation: transgenic alpha-1-antitrypsin (AAT), PPL therapeutics. Curr Opin Mol Ther. 2000 Apr;2(2):199-204. | |||||
REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018071) | |||||
REF 7 | Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone. J Med Chem. 2003 Aug 28;46(18):3865-76. | |||||
REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003114) | |||||
REF 9 | Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety. Bioorg Med Chem Lett. 2006 May 15;16(10):2641-7. | |||||
REF 10 | US patent application no. 2012,0251,516, PHARMACEUTICAL COMPOSITION FOR TREATING CANCER COMPRISING TRYPSINOGEN AND/OR CHYMOTRYPSINOGEN AND AN ACTIVE AGENT SELECTED FROM A SELENIUM COMPOUND, A VANILLOID COMPOUND AND A CYTOPLASMIC GLYCOLYSIS REDUCTION AGENT. | |||||
REF 11 | EP patent application no. 2490711, A pharmaceutical composition for treating cancer comprising trypsinogen and/or chymotrypsinogen and an active agent selected from a selenium compound, a vanilloid compound and a cytoplasmic glycolysis reduction agent). | |||||
REF 12 | Expression of human alpha 1 antitrypsin in transgenic sheep. Cytotechnology. 1992;9(1-3):77-84. | |||||
REF 13 | Arriva-ProMetic recombinant alpha 1-antitrypsin (rAAT) moves into the clinic for dermatology applications. ProMetic Life Sciences. 2009. | |||||
REF 14 | rAAt (inhaled) Arriva/Hyland Immuno. Curr Opin Mol Ther. 2006 Feb;8(1):76-82. | |||||
REF 15 | Optimization of the bioprocessing conditions for scale-up of transient production of a heterologous protein in plants using a chemically inducible viral amplicon expression system. Biotechnol Prog. 2009 May-Jun;25(3):722-34. | |||||
REF 16 | Bioreactor strategies for improving production yield and functionality of a recombinant human protein in transgenic tobacco cell cultures. Biotechnol Bioeng. 2009 Feb 1;102(2):508-20. | |||||
REF 17 | Inhibitors of serine proteases as potential therapeutic agents: the road from thrombin to tryptase to cathepsin G. J Med Chem. 2004 Feb 12;47(4):769-87. | |||||
REF 18 | Design and synthesis of conformationally constrained arginal thrombin inhibitors, Bioorg. Med. Chem. Lett. 7(17):2205-2210 (1997). | |||||
REF 19 | Effects of E-3123, a new protease inhibitor, on several protease activities and on experimental acute pancreatitis. Nihon Yakurigaku Zasshi. 1988 May;91(5):285-93. | |||||
REF 20 | Inhibition of serine proteases: activity of 1,3-diazetidine-2,4-diones. Bioorg Med Chem Lett. 2001 Jul 9;11(13):1691-4. | |||||
REF 21 | Aromatic amidines: comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin... J Med Chem. 1983 Feb;26(2):294-8. | |||||
REF 22 | Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasmi... J Med Chem. 2001 Aug 16;44(17):2753-71. | |||||
REF 23 | 2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease. J Med Chem. 1998 Mar 26;41(7):1060-7. | |||||
REF 24 | Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):817-22. | |||||
REF 25 | Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties. Bioorg Med Chem Lett. 2005 Jan 3;15(1):93-8. | |||||
REF 26 | Inhibitory effect of a conjugate between human urokinase and urinary trypsin inhibitor on tumor cell invasion in vitro. J Biol Chem. 1995 Apr 7;270(14):8361-6. | |||||
REF 27 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 28 | Non-covalent thrombin inhibitors featuring P(3)-heterocycles with P(1)-monocyclic arginine surrogates. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1203-8. | |||||
REF 29 | 5,5-trans lactone-containing inhibitors of serine proteases: identification of a novel, acylating thrombin inhibitor. Bioorg Med Chem Lett. 1998 Nov 3;8(21):2955-60. | |||||
REF 30 | Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. J Med Chem. 2009 Sep 24;52(18):5732-47. | |||||
REF 31 | Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'. Bioorg Med Chem Lett. 2003 Jan 20;13(2):161-4. | |||||
REF 32 | Novel thrombin inhibitors that are based on a macrocyclic tripeptide motif, Bioorg. Med. Chem. Lett. 6(24):2947-2952 (1996). | |||||
REF 33 | GRID/CPCA: a new computational tool to design selective ligands. J Med Chem. 2000 Aug 10;43(16):3033-44. | |||||
REF 34 | Synthesis and inhibition of human acrosin and trypsin and acute toxicity of aryl 4-guanidinobenzoates. J Med Chem. 1986 Apr;29(4):514-9. | |||||
REF 35 | Reduction in neutrophil elastase concentration by recombinant alphal-antitrypsin (recAAT) does not alter bacterial loading in the sputum of cystic ... Br J Biomed Sci. 2004;61(3):146-7. | |||||
REF 36 | In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1' subsite and its implications ... J Med Chem. 2005 Mar 24;48(6):1984-2008. | |||||
REF 37 | Structure-activity study of tripeptide thrombin inhibitors using alpha-alkyl amino acids and other conformationally constrained amino acid substitu... J Med Chem. 1995 Oct 27;38(22):4446-53. |
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