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

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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

Click to Show 3D Structure of This Target

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

[+] 29 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]

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]

L-375378

Drug Info

[30]

Macrocyclic tripeptide motif

Drug Info

[31]

Piperidine-1-carboxamidine

Drug Info

[32]

PMID3514912C9

Drug Info

[33]

RWJ-50353

Drug Info

[35]

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

Drug Info

[36]

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

[34]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Phosphonotyrosine

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF HUMAN TRYPSIN 1: UNEXPECTED PHOSPHORYLATION OF TYROSINE 151

PDB:1TRN

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[37]

PDB Sequence

IVGGYNCEEN

²⁵

SVPYQVSLNS

³⁷

GYHFCGGSLI

⁴⁷

NEQWVVSAGH

⁵⁷

CYKSRIQVRL

⁶⁷

GEHNIEVLEG

⁷⁸

NEQFINAAKI

⁸⁸

IRHPQYDRKT

⁹⁸

LNNDIMLIKL

¹⁰⁸

SSRAVINARV

¹¹⁸

STISLPTAPP

¹²⁹

ATGTKCLISG

¹⁴⁰

WGNTASSGAD

¹⁵⁰

PDELQCLDAP

¹⁶¹

VLSQAKCEAS

¹⁷¹

YPGKITSNMF

¹⁸¹

CVGFLEGGKD

¹⁸⁹

SCQGDSGGPV

¹⁹⁹

VCNGQLQGVV

²¹³

SWGDGCAQKN

²²³

KPGVYTKVYN

²³³

YVKWIKNTIA

²⁴³

ANS

Residue

Distance (Å)

TRP141

3.977

GLY142

3.898

ASN143

3.567

THR144

4.821

ALA149

3.630

Residue

Distance (Å)

ASP150

1.326

PRO152

1.345

ASP153

4.088

GLN192

2.855

Ligand Name: Isopropyl dihydrogen phosphate

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF HUMAN TRYPSIN 1: UNEXPECTED PHOSPHORYLATION OF TYROSINE 151

PDB:1TRN

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[37]

PDB Sequence

IVGGYNCEEN

²⁵

SVPYQVSLNS

³⁷

GYHFCGGSLI

⁴⁷

NEQWVVSAGH

⁵⁷

CYKSRIQVRL

⁶⁷

GEHNIEVLEG

⁷⁸

NEQFINAAKI

⁸⁸

IRHPQYDRKT

⁹⁸

LNNDIMLIKL

¹⁰⁸

SSRAVINARV

¹¹⁸

STISLPTAPP

¹²⁹

ATGTKCLISG

¹⁴⁰

WGNTASSGAD

¹⁵⁰

PDELQCLDAP

¹⁶¹

VLSQAKCEAS

¹⁷¹

YPGKITSNMF

¹⁸¹

CVGFLEGGKD

¹⁸⁹

SCQGDSGGPV

¹⁹⁹

VCNGQLQGVV

²¹³

SWGDGCAQKN

²²³

KPGVYTKVYN

²³³

YVKWIKNTIA

²⁴³

ANS

Residue

Distance (Å)

HIS57

2.949

SER190

3.944

CYS191

3.282

GLN192

3.423

GLY193

2.803

ASP194

3.448

Residue

Distance (Å)

SER195

1.586

VAL213

3.496

SER214

3.763

TRP215

3.795

GLY216

4.417

CYS220

4.951

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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 Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

Top

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 Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Pancreatic secretion	hsa04972	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Protein digestion and absorption	hsa04974	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

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

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 31

Novel thrombin inhibitors that are based on a macrocyclic tripeptide motif, Bioorg. Med. Chem. Lett. 6(24):2947-2952 (1996).

REF 32

GRID/CPCA: a new computational tool to design selective ligands. J Med Chem. 2000 Aug 10;43(16):3033-44.

REF 33

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 34

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 35

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 36

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.

REF 37

Crystal structure of human trypsin 1: unexpected phosphorylation of Tyr151. J Mol Biol. 1996 Jun 28;259(5):995-1010.

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