Target Information

Target General Information

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Target ID

T38509

Target Name

Coagulation factor XII (F12)

Synonyms

Hageman factor; HAF

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Gene Name

F12

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Innate/adaptive immunodeficiency [ICD-11: 4A00]

BioChemical Class

Peptidase

UniProt ID

FA12_HUMAN

EC Number

EC 3.4.21.38

Sequence

MRALLLLGFLLVSLESTLSIPPWEAPKEHKYKAEEHTVVLTVTGEPCHFPFQYHRQLYHK
CTHKGRPGPQPWCATTPNFDQDQRWGYCLEPKKVKDHCSKHSPCQKGGTCVNMPSGPHCL
CPQHLTGNHCQKEKCFEPQLLRFFHKNEIWYRTEQAAVARCQCKGPDAHCQRLASQACRT
NPCLHGGRCLEVEGHRLCHCPVGYTGAFCDVDTKASCYDGRGLSYRGLARTTLSGAPCQP
WASEATYRNVTAEQARNWGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDLAQCQTPTQ
AAPPTPVSPRLHVPLMPAQPAPPKPQPTTRTPPQSQTPGALPAKREQPPSLTRNGPLSCG
QRLRKSLSSMTRVVGGLVALRGAHPYIAALYWGHSFCAGSLIAPCWVLTAAHCLQDRPAP
EDLTVVLGQERRNHSCEPCQTLAVRSYRLHEAFSPVSYQHDLALLRLQEDADGSCALLSP
YVQPVCLPSGAARPSETTLCQVAGWGHQFEGAEEYASFLQEAQVPFLSLERCSAPDVHGS
SILPGMLCAGFLEGGTDACQGDSGGPLVCEDQAAERRLTLQGIISWGSGCGDRNKPGVYT
DVAYYLAWIREHTVS

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3D Structure

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AlphaFold

HIT2.0 ID

T21O8C

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

CSL312

Drug Info

Phase 3

Hereditary angioedema

[2]

ION547

Drug Info

Phase 1

Thrombosis

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

CSL312

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: Benzamidine

Ligand Info

Structure Description

Structures of the two-chain human plasma Factor XIIa co-crystallized with potent inhibitors

PDB:6B74

Method

X-ray diffraction

Resolution

2.32 Å

Mutation

[4]

PDB Sequence

VVGGLVALRG

²⁵

AHPYIAALYW

³⁷

GHSFCAGSLI

⁴⁷

APCWVLTAAH

⁵⁷

CLQDRPAPED

⁶³

LTVVLGQERR

⁷³

NHSCEPCQTL

⁸³

AVRSYRLHEA

⁹³

FSPVSYQHDL

¹⁰³

ALLRLQEDAD

^109D

GSCALLSPYV

¹¹⁸

QPVCLPSGAA

¹²⁸

RPSETTLCQV

¹³⁸

AGWGHQFEGA

¹⁴⁸

EEYASFLQEA

¹⁵⁸

QVPFLSLERC

¹⁶⁸

SAPDVHGSSI

¹⁷⁶

LPGMLCAGFL

¹⁸⁵

EGGTDACQGD

¹⁹⁴

SGGPLVCEDQ

²⁰⁴

AAERRLTLQG

²¹¹

IISWGSGCGD

^221A

RNKPGVYTDV

²³¹

AYYLAWIREH

²⁴¹

TVS

Residue

Distance (Å)

ASP189

2.782

ALA190

2.990

CYS191

3.878

GLN192

3.547

GLY193

4.973

SER195

3.619

ILE213

3.626

SER214

3.711

Residue

Distance (Å)

TRP215

3.542

GLY216

3.327

SER217

3.517

GLY219

2.584

CYS220

4.704

PRO225

4.763

GLY226

3.166

VAL227

4.487

Ligand Name: US10875851, Example 114

Ligand Info

Structure Description

Structure of human plasma factor XIIa in complex with (2S)-1-(N,3-dicyclohexyl-D-alanyl)-4-[(4R,5S)-4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-yl]-N-[(thiophen-2-yl)methyl]piperazine-2-carboxamide (compound 8h)

PDB:6X0T

Method

X-ray diffraction

Resolution

1.39 Å

Mutation

[5]

PDB Sequence

LSCGQRLRVV

³⁷⁴

GGLVALRGAH

³⁸⁴

PYIAALYWGH

³⁹⁴

SFCAGSLIAP

⁴⁰⁴

CWVLTAAHCL

⁴¹⁴

QDRPAPEDLT

⁴²⁴

VVLGQERRNH

⁴³⁴

SCEPCQTLAV

⁴⁴⁴

RSYRLHEAFS

⁴⁵⁴

PVSYQHDLAL

⁴⁶⁴

LRLQEDADGS

⁴⁷⁴

CALLSPYVQP

⁴⁸⁴

VCLPSLCQVA

⁵⁰³

GWGHQFEGAE

⁵¹³

EYASFLQEAQ

⁵²³

VPFLSLERCS

⁵³³

APDVHGSSIL

⁵⁴³

PGMLCAGFLE

⁵⁵³

GGTDACQGDS

⁵⁶³

GGPLVCEDQA

⁵⁷³

AERRLTLQGI

⁵⁸³

ISWGSGCGDR

⁵⁹³

NKPGVYTDVA

⁶⁰³

YYLAWIREHT

⁶¹³

Residue

Distance (Å)

TRP392

3.887

SER395

4.328

PHE396

3.404

CYS397

3.477

HIS412

3.402

CYS413

3.290

PRO455

4.143

VAL456

3.695

SER457

4.651

TYR458

3.539

GLU510

3.324

TYR515

4.597

ASP557

4.914

ALA558

3.837

Residue

Distance (Å)

CYS559

3.616

GLN560

3.288

GLY561

4.869

ASP562

4.892

SER563

3.143

ILE584

3.707

SER585

2.914

TRP586

3.151

GLY587

2.748

SER588

4.811

GLY589

3.598

CYS590

3.699

GLY597

4.574

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Protocadherin Fat 4 (FAT4)	PF00028 ; PF07645 ; PF12661 ; PF02210 More >>	31.496 (40/127)	8.49E-11
Protocadherin Fat 3 (FAT3)	PF00028 ; PF02210	28.814 (34/118)	7.54E-09
Aggrecan core protein (ACAN)	PF00059 ; PF00084 ; PF07686 ; PF00193 More >>	43.478 (20/46)	5.80E-04


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	7	Degree centrality	7.52E-04	Betweenness centrality	1.61E-04
Closeness centrality	1.88E-01	Radiality	1.32E+01	Clustering coefficient	2.38E-01
Neighborhood connectivity	9.43E+00	Topological coefficient	1.98E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

Clinical pipeline report, company report or official report of CSL Behring.

REF 2

ClinicalTrials.gov (NCT04656418) CSL312 (Garadacimab) in the Prevention of Hereditary Angioedema Attacks. U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT04934891) A Double-Blind, Placebo-Controlled, Dose-Escalation Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ION547 Administered Subcutaneously to Healthy Subjects. U.S.National Institutes of Health.

REF 4

Structures of human plasma beta-factor XIIa cocrystallized with potent inhibitors. Blood Adv. 2018 Mar 13;2(5):549-558.

REF 5

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