Target Information

Target General Information

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Target ID

T98022 (Former ID: TTDC00053)

Target Name

Carboxypeptidase B2 (CPB2)

Synonyms

Thrombin-activable fibrinolysis inhibitor; TAFI; Plasma carboxypeptidase B; Carboxypeptidase U; CPU; CPB2

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Gene Name

CPB2

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Cerebral ischaemia [ICD-11: 8B1Z]

Cerebral ischaemic stroke [ICD-11: 8B11]

Thrombosis [ICD-11: DB61-GB90]

Function

Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down- regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin.

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BioChemical Class

Peptidase

UniProt ID

CBPB2_HUMAN

EC Number

EC 3.4.17.20

Sequence

MKLCSLAVLVPIVLFCEQHVFAFQSGQVLAALPRTSRQVQVLQNLTTTYEIVLWQPVTAD
LIVKKKQVHFFVNASDVDNVKAHLNVSGIPCSVLLADVEDLIQQQISNDTVSPRASASYY
EQYHSLNEIYSWIEFITERHPDMLTKIHIGSSFEKYPLYVLKVSGKEQAAKNAIWIDCGI
HAREWISPAFCLWFIGHITQFYGIIGQYTNLLRLVDFYVMPVVNVDGYDYSWKKNRMWRK
NRSFYANNHCIGTDLNRNFASKHWCEEGASSSSCSETYCGLYPESEPEVKAVASFLRRNI
NQIKAYISMHSYSQHIVFPYSYTRSKSKDHEELSLVASEAVRAIEKISKNTRYTHGHGSE
TLYLAPGGGDDWIYDLGIKYSFTIELRDTGTYGFLLPERYIKPTCREAFAAVSKIAWHVI
RNV

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

DS-1040

Drug Info

Phase 1

Ischemic stroke

[3]

SAR-126119

Drug Info

Phase 1

Cerebrovascular ischaemia

[4]

UK-396082

Drug Info

Phase 1

Thrombosis

[5], [6]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

AZD-9684

Drug Info

Discontinued in Phase 2

Thrombosis

[7]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 1 Modulator drugs

DS-1040

Drug Info

[8]

Inhibitor

[+] 15 Inhibitor drugs

SAR-126119

Drug Info

[1]

UK-396082

Drug Info

[9]

AZD-9684

Drug Info

[10]

(+/-)-5-amino-2-(mercaptomethyl)pentanoic acid

Drug Info

[11]

2-(3-aminophenyl)-3-mercaptopropanoic acid

Drug Info

[12]

2-(3-guanidinophenyl)-3-mercaptopropanoic acid

Drug Info

[12]

2-(4-benzoylpiperidine-1-carbonyl)benzoic acid

Drug Info

[13]

3-mercapto-2-(piperidin-3-yl)propanoic acid

Drug Info

[12]

3-mercapto-2-(piperidin-4-yl)propanoic acid

Drug Info

[12]

6-Amino-2-(1H-imidazol-4-yl)-hexanoic acid

Drug Info

[14]

DL-benzylsuccinic acid

Drug Info

[13]

DL-guanidinoethylmercaptosuccinic acid

Drug Info

[13]

MN-462

Drug Info

[15]

PMID19954973C4

Drug Info

[9]

SQ-24798

Drug Info

[12]

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: Arginine

Ligand Info

Structure Description

Crystal structure of a T325I/T329I/H333Y/H335Q mutant of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI-IIYQ)

PDB:3D68

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

Yes

[16]

PDB Sequence

AQSGQVLAAL

¹⁰

PRTSRQVQVL

²⁰

QNLTTTYEIV

³⁰

LWQPVTADLI

⁴⁰

VKKKQVHFFV

⁵⁰

NASDVDNVKA

⁶⁰

HLNVSGIPCS

⁷⁰

VLLADVEDLI

⁸⁰

QQQISNDTVS

⁹⁰

PRASASYYEQ

¹⁰⁰

YHSLNEIYSW

¹¹⁰

IEFITERHPD

¹²⁰

MLTKIHIGSS

¹³⁰

FEKYPLYVLK

¹⁴⁰

VSGKEQTAKN

¹⁵⁰

AIWIDCGIHA

¹⁶⁰

REWISPAFCL

¹⁷⁰

WFIGHITQFY

¹⁸⁰

GIIGQYTNLL

¹⁹⁰

RLVDFYVMPV

²⁰⁰

VNVDGYDYSW

²¹⁰

KKNRMWRKNR

²²⁰

SFYANNHCIG

²³⁰

TDLNRNFASK

²⁴⁰

HWCEEGASSS

²⁵⁰

SCSETYCGLY

²⁶⁰

PESEPEVKAV

²⁷⁰

ASFLRRNINQ

²⁸⁰

IKAYISMHSY

²⁹⁰

SQHIVFPYSY

³⁰⁰

TRSKSKDHEE

³¹⁰

LSLVASEAVR

³²⁰

AIEKISKNIR

³³⁰

YTYGQGSETL

³⁴⁰

YLAPGGGDDW

³⁵⁰

IYDLGIKYSF

³⁶⁰

TIELRDTGTY

³⁷⁰

GFLLPERYIK

³⁸⁰

PTCREAFAAV

³⁹⁰

SKIAWHVIRN

⁴⁰⁰

Residue

Distance (Å)

HIS159

3.438

GLU162

4.133

ARG217

3.372

ASN234

2.724

ARG235

3.082

HIS288

3.992

SER289

4.258

VAL295

4.521

SER299

3.094

Residue

Distance (Å)

LEU340

3.590

TYR341

3.410

ALA343

3.362

GLY346

4.181

ASP348

2.787

ASP349

4.238

THR361

3.422

GLU363

3.107

Ligand Name: (2-Guanidinoethylmercapto)succinic acid

Ligand Info

Structure Description

Crystal structure of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) in complex with 2-guanidino-ethyl-mercaptosuccinic acid (GEMSA)

PDB:3D67

Method

X-ray diffraction

Resolution

3.40 Å

Mutation

[16]

PDB Sequence

AQSGQVLAAL

¹⁰

PRTSRQVQVL

²⁰

QNLTTTYEIV

³⁰

LWQPVTADLI

⁴⁰

VKKKQVHFFV

⁵⁰

NASDVDNVKA

⁶⁰

HLNVSGIPCS

⁷⁰

VLLADVEDLI

⁸⁰

QQQISNDTVS

⁹⁰

PRASASYYEQ

¹⁰⁰

YHSLNEIYSW

¹¹⁰

IEFITERHPD

¹²⁰

MLTKIHIGSS

¹³⁰

FEKYPLYVLK

¹⁴⁰

VSGKEQTAKN

¹⁵⁰

AIWIDCGIHA

¹⁶⁰

REWISPAFCL

¹⁷⁰

WFIGHITQFY

¹⁸⁰

GIIGQYTNLL

¹⁹⁰

RLVDFYVMPV

²⁰⁰

VNVDGYDYSW

²¹⁰

KKNRMWRKNR

²²⁰

SFYANNHCIG

²³⁰

TDLNRNFASK

²⁴⁰

HWCEEGASSS

²⁵⁰

SCSETYCGLY

²⁶⁰

PESEPEVKAV

²⁷⁰

ASFLRRNINQ

²⁸⁰

IKAYISMHSY

²⁹⁰

SQHIVFPYSY

³⁰⁰

TRSKSKDHEE

³¹⁰

LSLVASEAVR

³²⁰

AIEKTSKNTR

³³⁰

YTHGHGSETL

³⁴⁰

YLAPGGGDDW

³⁵⁰

IYDLGIKYSF

³⁶⁰

TIELRDTGTY

³⁷⁰

GFLLPERYIK

³⁸⁰

PTCREAFAAV

³⁹⁰

SKIAWHVIRN

⁴⁰⁰

Residue

Distance (Å)

VAL35

4.556

HIS159

2.891

GLU162

2.974

ARG217

3.135

ASP232

4.993

ASN234

3.185

ARG235

3.178

HIS288

2.890

SER289

3.209

VAL295

4.628

Residue

Distance (Å)

SER299

2.625

LEU340

3.964

TYR341

2.743

ALA343

3.913

GLY346

3.915

ASP348

2.664

ASP349

4.386

THR361

4.261

GLU363

2.806

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). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

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).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

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
Complement and coagulation cascades	hsa04610	Affiliated Target
Class: Organismal Systems => Immune system	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

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	2.92E-04
Closeness centrality	1.88E-01	Radiality	1.32E+01	Clustering coefficient	1.67E-01
Neighborhood connectivity	1.95E+01	Topological coefficient	2.68E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

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 Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Complement and coagulation cascades

Pancreatic secretion

Protein digestion and absorption

Panther Pathway

[+] 1 Panther Pathways

Plasminogen activating cascade

Reactome

[+] 1 Reactome Pathways

Metabolism of Angiotensinogen to Angiotensins

WikiPathways

[+] 1 WikiPathways

Complement and Coagulation Cascades

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

TAFIa inhibitors in the treatment of thrombosis. Curr Opin Drug Discov Devel. 2008 Jul;11(4):480-6.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028193)

REF 3

ClinicalTrials.gov (NCT02071004) DS1040b/Aspirin Drug/Drug Interaction Study. U.S. National Institutes of Health.

REF 4

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034720)

REF 5

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: 8657).

REF 6

ClinicalTrials.gov (NCT01091532) A Study In Healthy People Of Multiple Doses Of UK-396,082 Given By Mouth, To Investigate The Safety, Toleration And Time Course Of Blood Concentration Of UK-396,082 And Its Effects.. U.S. National Institutes of Health.

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018349)

REF 8

Clinical pipeline report, company report or official report of Daiichi Sankyo.

REF 9

Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor. Bioorg Med Chem Lett. 2010 Jan 1;20(1):92-6.

REF 10

Clinical pipeline report, company report or official report of AstraZeneca.

REF 11

Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis. J Med Chem. 2007 Nov 29;50(24):6095-103.

REF 12

3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa). Bioorg Med Chem Lett. 2007 Mar 1;17(5):1349-54.

REF 13

A new type of five-membered heterocyclic inhibitors of basic metallocarboxypeptidases. Eur J Med Chem. 2009 Aug;44(8):3266-71.

REF 14

Imidazole acetic acid TAFIa inhibitors: SAR studies centered around the basic P(1)(') group. Bioorg Med Chem Lett. 2004 May 3;14(9):2141-5.

REF 15

REF 16

Crystal structures of TAFI elucidate the inactivation mechanism of activated TAFI: a novel mechanism for enzyme autoregulation. Blood. 2008 Oct 1;112(7):2803-9.

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