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coagulation factor XI

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Target not currently curated in GtoImmuPdb

Target id: 2360

Nomenclature: coagulation factor XI

Family: Blood coagulation components, S1: Chymotrypsin

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 625 4q35.2 F11 coagulation factor XI
Mouse - 624 8 25.14 cM F11 coagulation factor XI
Rat - 556 16q11 F11 coagulation factor XI
Previous and Unofficial Names Click here for help
Cf11 | FXI | plasma thromboplastin antecedent | PTA
Database Links Click here for help
Specialist databases
MEROPS S01.213 (Hs)
Other databases
Alphafold P03951 (Hs), Q91Y47 (Mm)
BRENDA 3.4.21.27
ChEMBL Target CHEMBL2820 (Hs)
DrugBank Target P03951 (Hs)
Ensembl Gene ENSG00000088926 (Hs), ENSMUSG00000031645 (Mm), ENSRNOG00000013684 (Rn)
Entrez Gene 2160 (Hs), 109821 (Mm), 290757 (Rn)
Human Protein Atlas ENSG00000088926 (Hs)
KEGG Enzyme 3.4.21.27
KEGG Gene hsa:2160 (Hs), mmu:109821 (Mm), rno:290757 (Rn)
OMIM 264900 (Hs)
Orphanet ORPHA121660 (Hs)
Pharos P03951 (Hs)
RefSeq Nucleotide NM_000128 (Hs), NM_028066 (Mm), NM_001047848 (Rn)
RefSeq Protein NP_000119 (Hs), NP_082342 (Mm), NP_001041313 (Rn)
UniProtKB P03951 (Hs), Q91Y47 (Mm)
Wikipedia F11 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Factor XIa in Complex with Compound 3f
PDB Id:  7V18
Ligand:  FXIa inhibitor 3f
Resolution:  1.73Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 3.4.21.27

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
milvexian Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 10.0 pKi 1
⤷ pKi 10.0 (Ki 1.1x10-10 M) [1]
Description: Assay using purified human F11a
FXIa inhibitor 3f Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.8 pKi 11
⤷ pKi 9.8 (Ki 1.7x10-10 M) [11]
Description: Inhibition of purified human enzyme in vitro
EP-7041 Small molecule or natural product Hs Inhibition 8.1 pIC50 7
⤷ pIC50 8.1 (IC50 7.1x10-9 M) [7]
Description: Inhibition of activated human factor XI (XIa)
alpha-ketothiazole analogue 36 Small molecule or natural product Hs Inhibition 7.5 pIC50 4
⤷ pIC50 7.5 (IC50 3x10-8 M) [4]
Inhibitor Comments
BMS-962212 is a small molecule FXIa inhibitor - Ki 0.7 nM [6]. Asundexian (BAY 2433334) inhibits FXIa activity in vitro with an IC50 of 0.92 nM [3].
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
abelacimab Peptide Hs Binding 11.3 – 11.9 pKd 10
⤷ pKd 11.9 (Kd 1.3x10-12 M) [10]
Description: Binding to human FXI
pKd 11.3 (Kd 4.7x10-12 M) [10]
Description: Binding to human FXIa
osocimab Peptide Hs Inhibition 8.6 pKd 9
⤷ pKd 8.6 (Kd 2.4x10-9 M) [9]
Description: Binding affinity by SPR
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Factor XI deficiency
Description: Hemophilia C is caused by autosomal recessive FXI deficiency and is associated with bleeding, although the bleeding pattern is unpredictable (or inconsistent) compared to hemophilias A and B. Bleeding events occur after surgery or injury, and trauma to the mucocutaneous lining of the oral or nasal cavities and the urinary tract is often the source of bleeding.
Synonyms: hemophilia C
plasma thromboplastin antecedent (PTA) deficiency
Rosenthal syndrome
Disease Ontology: DOID:2229
OMIM: 612416
Orphanet: ORPHA329
General Comments
FXI is the inactive proenzyme (or zymogen) of the plasma serine protease activated FXI (FXIa). FXI can be activated by FXIIa, thrombin, or FXIa. FXIa activates FIX to FIXa which in turn activates FX. FXI is produced in the liver and circulates as a homodimer.
FXIa contributes to thrombin generation and thrombus formation. Epidemiologic studies show that an elevated level of FXI is associated with an increased risk of venous thrombosis [5], and in contrast, FXI deficiency is associated with a reduced thrombosis risk [8]. These findings and results from experimental studies have linked FXI to thromboembolic disease, and suggest that FXI and/or FXIa inhibition may offer a novel approach for the development of antithrombotic therapeutics that would not impair normal hemostasis [2].

References

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1. Dilger AK, Pabbisetty KB, Corte JR, De Lucca I, Fang T, Yang W, Pinto DJP, Wang Y, Zhu Y, Mathur A et al.. (2022) Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy. J Med Chem, 65 (3): 1770-1785. [PMID:34494428]

2. Gailani D, Gruber A. (2016) Factor XI as a Therapeutic Target. Arterioscler Thromb Vasc Biol, 36 (7): 1316-22. [PMID:27174099]

3. Jiminez Nunez E, Ackerstaff J, Rohrig S, Hillisch A, Meier K, Heitmeier S, Tersteegen A, Stampfuss J, Ellerbrock P, Melbom D et al.. (2017) Substituted oxopyridine derivatives. Patent number: WO2017005725A1. Assignee: Bayer Pharma. Priority date: 09/07/2015. Publication date: 12/01/2017.

4. Maryanoff BE, Costanzo MJ. (2008) Inhibitors of proteases and amide hydrolases that employ an alpha-ketoheterocycle as a key enabling functionality. Bioorg Med Chem, 16 (4): 1562-95. [PMID:18053726]

5. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. (2000) High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med, 342 (10): 696-701. [PMID:10706899]

6. Pinto DJP, Orwat MJ, Smith 2nd LM, Quan ML, Lam PYS, Rossi KA, Apedo A, Bozarth JM, Wu Y, Zheng JJ et al.. (2017) Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212). J Med Chem, 60 (23): 9703-9723. [PMID:29077405]

7. Pollack Jr CV, Kurz MA, Hayward NJ. (2020) EP-7041, a Factor XIa Inhibitor as a Potential Antithrombotic Strategy in Extracorporeal Membrane Oxygenation: A Brief Report. Crit Care Explor, 2 (9): e0196. [PMID:32984829]

8. Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. (2008) Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood, 111 (8): 4113-7. [PMID:18268095]

9. Schaefer M, Buchmueller A, Dittmer F, Straßburger J, Wilmen A. (2019) Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI. J Mol Biol, 431 (24): 4817-4833. [PMID:31655039]

10. Weitz JI, Chan NC. (2019) MAA868 locks factor XIa in a zymogen-like state. Blood, 133 (13): 1393-1394. [PMID:30923107]

11. Xu G, Liu Z, Wang X, Lu T, DesJarlais RL, Thieu T, Zhang J, Devine ZH, Du F, Li Q et al.. (2022) Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions. J Med Chem, 65 (15): 10419-10440. [PMID:35862732]

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