Target Information

Target General Information

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Target ID

T27602 (Former ID: TTDS00282)

Target Name

Cationic trypsinogen (PRSS1)

Synonyms

Trypsin-1; Trypsin I; TRYP1; TRY1; TRP1; Serine protease 1; Beta-trypsin

Gene Name

PRSS1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Mature B-cell lymphoma [ICD-11: 2A85]

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.

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BioChemical Class

Peptidase

UniProt ID

TRY1_HUMAN

EC Number

EC 3.4.21.4

Sequence

MNPLLILTFVAAALAAPFDDDDKIVGGYNCEENSVPYQVSLNSGYHFCGGSLINEQWVVS
AGHCYKSRIQVRLGEHNIEVLEGNEQFINAAKIIRHPQYDRKTLNNDIMLIKLSSRAVIN
ARVSTISLPTAPPATGTKCLISGWGNTASSGADYPDELQCLDAPVLSQAKCEASYPGKIT
SNMFCVGFLEGGKDSCQGDSGGPVVCNGQLQGVVSWGDGCAQKNKPGVYTKVYNYVKWIK
NTIAANS

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3D Structure

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PDB

HIT2.0 ID

T39YFG

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Bortezomib

Drug Info

Approved

Multiple myeloma

[2], [3]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

Ulinastatin

Drug Info

Phase 3

Premature labour

[4]

Alpha-1 antitrypsin

Drug Info

Phase 2

Coagulation defect

[5]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

Dermolastin

Drug Info

Discontinued in Phase 2

Atopic dermatitis

[6]

RWJ-56423

Drug Info

Discontinued in Phase 1

Asthma

[7]

Patamostat

Drug Info

Terminated

Hypotension

[8]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 31 Inhibitor drugs

Bortezomib

Drug Info

[1]

MELAGATRAN

Drug Info

[9]

Dermolastin

Drug Info

[13], [14], [15], [16]

RWJ-56423

Drug Info

[17]

BMY-44621

Drug Info

[18]

1,3-Di-p-tolyl-[1,3]diazetidine-2,4-dione

Drug Info

[20]

1,3-Dibenzyl-[1,3]diazetidine-2,4-dione

Drug Info

[20]

1-(3-Amino-benzyl)-1H-indole-5-carboxamidine

Drug Info

[21]

1-(3-Nitro-benzyl)-1H-indole-5-carboxamidine

Drug Info

[21]

1-Benzyl-1H-indole-5-carboxamidine

Drug Info

[21]

2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine

Drug Info

[22]

2-(2-Iodo-phenyl)-benzo[d][1,3]oxazin-4-one

Drug Info

[23]

2-Propionyl-1H-indole-6-carboxamidine

Drug Info

[21]

4-(3,4-Diethoxy-benzylamino)-benzamidine

Drug Info

[24]

4-(4-Benzyloxy-3-methoxy-benzylamino)-benzamidine

Drug Info

[24]

4-(5-Nitro-indol-1-ylmethyl)-benzamidine

Drug Info

[21]

4-Indol-1-ylmethyl-benzamidine

Drug Info

[21]

6-Styryl-naphthalene-2-carboxamidine

Drug Info

[25]

8-Bromo-6-styryl-naphthalene-2-carboxamidine

Drug Info

[25]

8-Furan-3-yl-6-styryl-naphthalene-2-carboxamidine

Drug Info

[25]

Benzamidine

Drug Info

[27]

CVS-2139

Drug Info

[28]

CVS-2359

Drug Info

[28]

GR-133686

Drug Info

[29]

Grassystatin a

Drug Info

[30]

L-375378

Drug Info

[31]

Macrocyclic tripeptide motif

Drug Info

[32]

Piperidine-1-carboxamidine

Drug Info

[33]

PMID3514912C9

Drug Info

[34]

RWJ-50353

Drug Info

[36]

Tert-butyloxy carbonyl-D-Phe-pro-Arg-H

Drug Info

[37]

Modulator

[+] 7 Modulator drugs

Ulinastatin

Drug Info

[4]

Alpha-1 antitrypsin

Drug Info

[10], [11], [12]

Patamostat

Drug Info

[10], [11], [19]

ATF-HI-8

Drug Info

[26]

JBP-1

Drug Info

[10], [11]

POP-1

Drug Info

[10], [11]

recAAT, PPL Therapeutics/Bayer

Drug Info

[35]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 4 KEGG Pathways

Neuroactive ligand-receptor interaction

Pancreatic secretion

Protein digestion and absorption

Influenza A

Reactome

[+] 2 Reactome Pathways

Activation of Matrix Metalloproteinases

Cobalamin (Cbl, vitamin B12) transport and metabolism

WikiPathways

[+] 1 WikiPathways

Activation of Matrix Metalloproteinases

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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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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