Target Information

Target General Information

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Target ID

T46040 (Former ID: TTDI01964)

Target Name

Coagulation factor XI (F11)

Synonyms

Plasma thromboplastin antecedent; PTA; FXI

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Gene Name

F11

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Clotting disorder ICD-11: 3B4Z

Cerebral ischaemic stroke [ICD-11: 8B11]

Function

Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.

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BioChemical Class

Peptidase

UniProt ID

FA11_HUMAN

EC Number

EC 3.4.21.27

Sequence

MIFLYQVVHFILFTSVSGECVTQLLKDTCFEGGDITTVFTPSAKYCQVVCTYHPRCLLFT
FTAESPSEDPTRWFTCVLKDSVTETLPRVNRTAAISGYSFKQCSHQISACNKDIYVDLDM
KGINYNSSVAKSAQECQERCTDDVHCHFFTYATRQFPSLEHRNICLLKHTQTGTPTRITK
LDKVVSGFSLKSCALSNLACIRDIFPNTVFADSNIDSVMAPDAFVCGRICTHHPGCLFFT
FFSQEWPKESQRNLCLLKTSESGLPSTRIKKSKALSGFSLQSCRHSIPVFCHSSFYHDTD
FLGEELDIVAAKSHEACQKLCTNAVRCQFFTYTPAQASCNEGKGKCYLKLSSNGSPTKIL
HGRGGISGYTLRLCKMDNECTTKIKPRIVGGTASVRGEWPWQVTLHTTSPTQRHLCGGSI
IGNQWILTAAHCFYGVESPKILRVYSGILNQSEIKEDTSFFGVQEIIIHDQYKMAESGYD
IALLKLETTVNYTDSQRPICLPSKGDRNVIYTDCWVTGWGYRKLRDKIQNTLQKAKIPLV
TNEECQKRYRGHKITHKMICAGYREGGKDACKGDSGGPLSCKHNEVWHLVGITSWGEGCA
QRERPGVYTNVVEYVDWILEKTQAV

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 7 Clinical Trial Drugs

A186

Drug Info

IND submitted

Clotting disorder

[2]

Asundexian

Drug Info

Phase 3

Ischemic stroke

[3]

Abelacimab

Drug Info

Phase 2

Atrial fibrillation

[4]

MK-2060

Drug Info

Phase 2

Thrombosis

[5]

A336

Drug Info

Phase 1

Clotting disorder

[2]

AB023

Drug Info

Phase 1

End-stage renal disease

[6]

EP-7041

Drug Info

Phase 1

Thrombosis

[1]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 5 Inhibitor drugs

Asundexian

Drug Info

[7]

Abelacimab

Drug Info

[8]

MK-2060

Drug Info

[9]

AB023

Drug Info

[10]

EP-7041

Drug Info

[1]

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: Glutathione

Ligand Info

Structure Description

Crystal Structure of the Catalytic Domain of the Coagulation Factor XIa in Complex with Benzamidine (S434A-T475A-K437 Mutant)

PDB:1ZHM

Method

X-ray diffraction

Resolution

1.96 Å

Mutation

Yes

[11]

PDB Sequence

IVGGTASVRG

²⁵

EWPWQVTLHT

³⁵

TSPTQRHLCG

⁴¹

GSIIGNQWIL

⁵³

TAAHCFYGVE

⁶⁰

SPKILRVYSG

⁷⁰

ILNQAEIAED

⁸⁰

TSFFGVQEII

⁸⁹

IHDQYKMAES

⁹⁹

GYDIALLKLE

¹⁰⁹

TTVNYADSQR

¹¹⁹

PICLPSKGDR

¹³⁰

NVIYTDCWVT

¹³⁹

GWGYRKLRDK

¹⁴⁹

IQNTLQKAKI

¹⁶⁰

PLVTNEECQK

¹⁷⁰

RYRGHKITHK

¹⁷⁹

MICAGYREGG

¹⁸⁸

KDACKGDSGG

¹⁹⁷

PLSCKHNEVW

²⁰³

HLVGITSWGE

²¹⁷

GCAQRERPGV

²²⁷

YTNVVEYVDW

²³⁷

ILEKTQA

Residue

Distance (Å)

TRP29

3.836

ARG119

3.178

PRO121

3.022

ILE122

3.690

Residue

Distance (Å)

CYS123

2.041

VAL202D

3.689

GLU202C

4.280

TRP203

2.903

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: BMS-986177

Ligand Info

Structure Description

FACTOR XIA (PICHIA PASTORIS; C500S [C122S]) IN COMPLEX WITH THE INHIBITOR Milvexian (BMS-986177), IUPAC NAME:(6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- oxopyrimidin-1(6H)-yl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-15,11- (metheno)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one

PDB:7MBO

Method

X-ray diffraction

Resolution

0.92 Å

Mutation

Yes

[12]

PDB Sequence

IVGGTASVRG

²⁵

EWPWQVTLHT

³⁵

TSPTQRHLCG

⁴³

GSIIGNQWIL

⁵³

TAAHCFYGVE

⁶¹

SPKILRVYSG

⁶⁹

ILNQSEIKED

⁷⁹

TSFFGVQEII

⁸⁹

IHDQYKMAES

⁹⁹

GYDIALLKLE

¹⁰⁹

TTVNYTDSQR

¹¹⁹

PISLPSKGDR

¹²⁹

NVIYTDCWVT

¹³⁹

GWGYRKLRDK

¹⁵⁰

IQNTLQKAKI

¹⁶⁰

PLVTNEECQK

¹⁶⁹

RYRGHKITHK

¹⁷⁹

MICAGYREGG

¹⁸⁷

KDACKGDSGG

¹⁹⁷

PLSCKHNEVW

²⁰⁷

HLVGITSWGE

²¹⁷

GCAQRERPGV

²²⁷

YTNVVEYVDW

²³⁷

ILEKTQA

Residue

Distance (Å)

ARG39

3.314

HIS40

2.448

LEU41

1.933

CYS42

3.290

HIS57

2.254

CYS58

2.615

TYR58B

3.996

PHE58A

4.537

GLY59

4.598

TYR143

2.923

LEU147

2.948

ILE151

3.020

ASP189

2.730

ALA190

2.880

CYS191

2.690

LYS192

2.525

Residue

Distance (Å)

GLY193

2.098

ASP194

2.762

SER195

2.047

THR213

2.495

SER214

3.431

TRP215

3.148

GLY216

2.685

GLU217

3.847

GLY218

2.466

CYS219

3.092

ALA220

4.361

PRO225

4.737

GLY226

2.525

VAL227

3.084

TYR228

3.688

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

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

Degree	9	Degree centrality	9.67E-04	Betweenness centrality	3.51E-05
Closeness centrality	1.77E-01	Radiality	1.29E+01	Clustering coefficient	3.61E-01
Neighborhood connectivity	1.18E+01	Topological coefficient	2.26E-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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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

Clinical pipeline report, company report or official report of Klus Pharma

REF 3

ClinicalTrials.gov (NCT05686070) A Multicenter, International, Randomized, Placebo Controlled, Double-blind, Parallel Group and Event Driven Phase 3 Study of the Oral FXIa Inhibitor Asundexian (BAY 2433334) for the Prevention of Ischemic Stroke in Male and Female Participants Aged 18 Years and Older After an Acute Non-cardioembolic Ischemic Stroke or High-risk TIA. U.S.National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT04755283) A Multicenter, RandomiZed, Active-ControLled Study to Evaluate the Safety and Tolerability of Two Blinded Doses of Abelacimab (MAA868) Compared With Open-Label Rivaroxaban in Patients With Atrial Fibrillation (AZALEA). U.S.National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT05027074) A Randomized Parallel-group, Placebo-controlled, Double-blind, Event-driven, Multi-center Phase 2 Clinical Outcome Trial of Prevention of Arteriovenous Graft Thrombosis and Safety of MK-2060 in Patients With End Stage Renal Disease Receiving Hemodialysis. U.S.National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT03097341) Safety and Tolerability Study of Xisomab 3G3 in Healthy Adult Subjects. U.S. National Institutes of Health.

REF 7

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa. J Thromb Haemost. 2022 Jun;20(6):1400-1411.

REF 8

Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa. J Thromb Haemost. 2022 Feb;20(2):307-315.

REF 9

Clinical pipeline report, company report or official report of MSD

REF 10

Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial. Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):799-809.

REF 11

Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors. Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25.

REF 12

Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy. J Med Chem. 2022 Feb 10;65(3):1770-1785.

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