Target Information

Target General Infomation
Target ID
T27602
Former ID
TTDS00282
Target Name
Trypsin
Gene Name
PRSS1
Synonyms
Trypsinogen; PRSS1
Target Type
Clinical Trial
Disease Atopic dermatitis [ICD9: 691.8, 692.9; ICD10: L00-L99]
Asthma [ICD10: J45]
Blood coagulation disorders [ICD10: D65-D68]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hypotension [ICD9: 458, 796.3; ICD10: I95]
Premature labour [ICD9: 644, 765; ICD10: O60.1, P07.3]
Unspecified [ICD code not available]
BioChemical Class
Peptidase
Target Validation
T27602
UniProt ID
P07477
EC Number
EC 3.4.21.4
Sequence
MNPLLILTFVAAALAAPFDDDDKIVGGYNCEENSVPYQVSLNSGYHFCGGSLINEQWVVS
AGHCYKSRIQVRLGEHNIEVLEGNEQFINAAKIIRHPQYDRKTLNNDIMLIKLSSRAVIN
ARVSTISLPTAPPATGTKCLISGWGNTASSGADYPDELQCLDAPVLSQAKCEASYPGKIT
SNMFCVGFLEGGKDSCQGDSGGPVVCNGQLQGVVSWGDGCAQKNKPGVYTKVYNYVKWIK
NTIAANS
Drugs and Mode of Action
Drug(s) MELAGATRAN Drug Info Phase 3 Discovery agent [1], [2]
Ulinastatin Drug Info Phase 3 Premature labour [3]
Alpha-1 antitrypsin Drug Info Phase 2 Blood coagulation disorders [4]
Dermolastin Drug Info Discontinued in Phase 2 Atopic dermatitis [5]
RWJ-56423 Drug Info Discontinued in Phase 1 Asthma [6]
BMY-44621 Drug Info Terminated Discovery agent [7]
Patamostat Drug Info Terminated Hypotension [8]
Inhibitor 1,3-Di-p-tolyl-[1,3]diazetidine-2,4-dione Drug Info [9]
1,3-Dibenzyl-[1,3]diazetidine-2,4-dione Drug Info [9]
1-(3-Amino-benzyl)-1H-indole-5-carboxamidine Drug Info [10]
1-(3-Nitro-benzyl)-1H-indole-5-carboxamidine Drug Info [10]
1-Benzyl-1H-indole-5-carboxamidine Drug Info [10]
2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine Drug Info [11]
2-(2-Iodo-phenyl)-benzo[d][1,3]oxazin-4-one Drug Info [12]
2-Propionyl-1H-indole-6-carboxamidine Drug Info [10]
4-(3,4-Diethoxy-benzylamino)-benzamidine Drug Info [13]
4-(4-Benzyloxy-3-methoxy-benzylamino)-benzamidine Drug Info [13]
4-(5-Nitro-indol-1-ylmethyl)-benzamidine Drug Info [10]
4-Indol-1-ylmethyl-benzamidine Drug Info [10]
6-Styryl-naphthalene-2-carboxamidine Drug Info [14]
8-Bromo-6-styryl-naphthalene-2-carboxamidine Drug Info [14]
8-Furan-3-yl-6-styryl-naphthalene-2-carboxamidine Drug Info [14]
Benzamidine Drug Info [15]
Benzamidrazone analogue Drug Info [16]
BMY-44621 Drug Info [17]
compound 9 Drug Info [18]
CVS-2139 Drug Info [19]
CVS-2359 Drug Info [19]
Dermolastin Drug Info [20], [21], [22], [23]
GR-133686 Drug Info [24]
GRASSYSTATIN A Drug Info [25]
L-375378 Drug Info [26]
Macrocyclic tripeptide motif Drug Info [27]
MELAGATRAN Drug Info [28]
P1 argininal derivative Drug Info [29]
Peptide boronate Drug Info [30]
Piperidine-1-carboxamidine Drug Info [31]
RWJ-50353 Drug Info [32]
RWJ-56423 Drug Info [33]
Tert-butyloxy carbonyl-D-Phe-pro-Arg-H Drug Info [34]
Modulator Alpha-1 antitrypsin Drug Info [35], [36], [37]
ATF-HI-8 Drug Info
JBP-1 Drug Info [36], [37]
Patamostat Drug Info [38], [36], [37]
POP-1 Drug Info [36], [37]
recAAT, PPL Therapeutics/Bayer Drug Info
Ulinastatin Drug Info [3]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
DRM DRM Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Pancreatic secretion
Protein digestion and absorption
Influenza A
Reactome Activation of Matrix Metalloproteinases
Cobalamin (Cbl, vitamin B12) transport and metabolism
WikiPathways Activation of Matrix Metalloproteinases
References
REF 1ClinicalTrials.gov (NCT00206089) Melagatran/Ximelagatran Versus Enoxaparin for the Prevention of Venous Thromboembolic Events. U.S. National Institutes of Health.
REF 2(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: 6382).
REF 3Intravenous 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 4Technology evaluation: transgenic alpha-1-antitrypsin (AAT), PPL therapeutics. Curr Opin Mol Ther. 2000 Apr;2(2):199-204.
REF 5Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018071)
REF 6Potent, 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 7Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003308)
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003114)
REF 9Bioorg Med Chem Lett. 2001 Jul 9;11(13):1691-4.Inhibition of serine proteases: activity of 1,3-diazetidine-2,4-diones.
REF 10J Med Chem. 1983 Feb;26(2):294-8.Aromatic amidines: comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin.
REF 11J Med Chem. 2001 Aug 16;44(17):2753-71.Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasminogen activator and factor Xa.
REF 12J Med Chem. 1998 Mar 26;41(7):1060-7.2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease.
REF 13Bioorg Med Chem Lett. 2005 Feb 1;15(3):817-22.Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors.
REF 14Bioorg Med Chem Lett. 2005 Jan 3;15(1):93-8.Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties.
REF 15How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 16Bioorg Med Chem Lett. 1999 Sep 6;9(17):2483-6.Fluorobenzamidrazone thrombin inhibitors: influence of fluorine on enhancing oral absorption.
REF 17Design and synthesis of conformationally constrained arginal thrombin inhibitors, Bioorg. Med. Chem. Lett. 7(17):2205-2210 (1997).
REF 18Synthesis and inhibition of human acrosin and trypsin and acute toxicity of aryl 4-guanidinobenzoates. J Med Chem. 1986 Apr;29(4):514-9.
REF 19Bioorg Med Chem Lett. 2002 Apr 22;12(8):1203-8.Non-covalent thrombin inhibitors featuring P(3)-heterocycles with P(1)-monocyclic arginine surrogates.
REF 20rAAt (inhaled) Arriva/Hyland Immuno. Curr Opin Mol Ther. 2006 Feb;8(1):76-82.
REF 21Bioreactor 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 22Optimization 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 23Arriva-ProMetic recombinant alpha 1-antitrypsin (rAAT) moves into the clinic for dermatology applications. ProMetic Life Sciences. 2009.
REF 24Bioorg Med Chem Lett. 1998 Nov 3;8(21):2955-60.5,5-trans lactone-containing inhibitors of serine proteases: identification of a novel, acylating thrombin inhibitor.
REF 25J Med Chem. 2009 Sep 24;52(18):5732-47.Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation.
REF 26Bioorg Med Chem Lett. 2003 Jan 20;13(2):161-4.Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'.
REF 27Novel thrombin inhibitors that are based on a macrocyclic tripeptide motif, Bioorg. Med. Chem. Lett. 6(24):2947-2952 (1996).
REF 28Bioorg Med Chem Lett. 2006 May 15;16(10):2641-7. Epub 2006 Mar 6.Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety.
REF 29Bioorg Med Chem Lett. 2002 Mar 11;12(5):743-8.Novel, potent non-covalent thrombin inhibitors incorporating p(3)-lactam scaffolds.
REF 30J Med Chem. 1995 Apr 28;38(9):1511-22.Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin.
REF 31J Med Chem. 2000 Aug 10;43(16):3033-44.GRID/CPCA: a new computational tool to design selective ligands.
REF 32J Med Chem. 2005 Mar 24;48(6):1984-2008.In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1' subsite and its implications to structure-based drug design.
REF 33J Med Chem. 2004 Feb 12;47(4):769-87.Inhibitors of serine proteases as potential therapeutic agents: the road from thrombin to tryptase to cathepsin G.
REF 34J Med Chem. 1995 Oct 27;38(22):4446-53.Structure-activity study of tripeptide thrombin inhibitors using alpha-alkyl amino acids and other conformationally constrained amino acid substitutions.
REF 35Expression of human alpha 1 antitrypsin in transgenic sheep. Cytotechnology. 1992;9(1-3):77-84.
REF 36US 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 37EP 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 38Effects 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.

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