F9

Summary

F9 (coagulation factor IX, HGNC:3551) is a protein-coding gene on chromosome Xq27.1, encoding Coagulation factor IX (P00740). Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes vitamin K-dependent coagulation factor IX that circulates in the blood as an inactive zymogen. This factor is converted to an active form by factor XIa, which excises the activation peptide and thus generates a heavy chain and a light chain held together by one or more disulfide bonds. The role of this activated factor IX in the blood coagulation cascade is to activate factor X to its active form through interactions with Ca+2 ions, membrane phospholipids, and factor VIII. Alterations of this gene, including point mutations, insertions and deletions, cause factor IX deficiency, which is a recessive X-linked disorder, also called hemophilia B or Christmas disease. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing.

Source: NCBI Gene 2158 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemophilia B (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 699 total — 208 pathogenic, 102 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000133

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3551
Approved symbol	F9
Name	coagulation factor IX
Location	Xq27.1
Locus type	gene with protein product
Status	Approved
Aliases	FIX
Ensembl gene	ENSG00000101981
Ensembl biotype	protein_coding
OMIM	300746
Entrez	2158

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000218099, ENST00000394090, ENST00000479617, ENST00000643157

RefSeq mRNA: 2 — MANE Select: NM_000133 NM_000133, NM_001313913

CCDS: CCDS14666, CCDS83495

Canonical transcript exons

ENST00000218099 — 8 exons

Exon	Start	End
ENSE00000677287	139537010	139537173
ENSE00001029145	139561524	139563459
ENSE00001173311	139560741	139560855
ENSE00001173315	139551062	139551264
ENSE00001173320	139548363	139548491
ENSE00001173327	139541076	139541189
ENSE00001173335	139537362	139537386
ENSE00003674048	139530739	139530852

Expression profiles

Bgee: expression breadth broad, 45 present calls, max score 98.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.6727 / max 1225.1303, expressed in 10 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197749	2.6727	10

Top tissues by expression

257 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.70	gold quality
liver	UBERON:0002107	98.49	gold quality
secondary oocyte	CL:0000655	67.54	gold quality
oocyte	CL:0000023	65.46	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	59.31	gold quality
endometrium epithelium	UBERON:0004811	54.60	gold quality
cranial nerve II	UBERON:0000941	51.11	silver quality
frontal pole	UBERON:0002795	50.41	gold quality
quadriceps femoris	UBERON:0001377	50.38	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
tibialis anterior	UBERON:0001385	50.21	silver quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
pancreatic ductal cell	CL:0002079	49.94	silver quality
thymus	UBERON:0002370	49.51	gold quality
vastus lateralis	UBERON:0001379	49.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
deltoid	UBERON:0001476	49.24	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
ileal mucosa	UBERON:0000331	49.10	silver quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
oviduct epithelium	UBERON:0004804	48.41	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, GABPA, HNF4A, NR2F2

miRNA regulators (miRDB)

88 targeting F9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AZ-3P	99.82	70.56	3549

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Asn346Asp results in dysfunctional protein with defective factor VIIIa interaction. (PMID:11583320)
• Mutations in the factor IX gene (F9) during the past 150 years have relative rates similar to ancient mutations. (PMID:11754103)
• role of EGF-like domains in stimulation by factor VIIIa and it’s isolated A2 domain (PMID:11925427)
• increased procoagulant activity due to formation of additional fVIII phosphatidylserine binding sites on the outer surface of oxLDL-treated cells and higher binding affinity between components of the Xase complex, activated factors VIII and IX. (PMID:12036878)
• Circulating and binding characteristics of human wild-type factor IX and certain Gla domain mutants injected into factor IX-deficient mice in in vivo models and applied to human artery specimens. (PMID:12070021)
• determination of role of EGF1 of activated factor IX in direct binding to activated factor VIII (PMID:12105230)
• a three-dimensional model of the ternary complex between FVIIa:TF:FIX was built using a full-space search algorithm in combination with computational graphics (PMID:12152682)
• Data show that the rate of factor IX activation by factor XIa is not enhanced by biological surfaces, and activated platelet surfaces are thrombogenic while endothelial surfaces are not. (PMID:12167623)
• F9 is activated by interaction with the erythrocyte membrane, causing intrinsic coagulation (PMID:12192300)
• role of factor IX gamma-carboxyglutamic acid domain in interactions between factor IX and factor XIa (PMID:12496253)
• restriction fragment length polymorphisms of FIX gene may be useful markers for carrier detection and prenatal diagnosis in Chinese families with hemophilia B patients (PMID:12513796)
• Low density lipoprotein receptor-related protein and factor IXa share structural requirements for binding to the A3 domain of coagulation factor VIII (PMID:12522143)
• activated coagulation factor IX binds to low density lipoprotein receptor-related protein via residues phe342-asn346 (PMID:12522212)
• A model of the FIXa-FVIIIa complex was constructed and indicated that EGF1 of FIXa does not interact directly with FVIIIa. (PMID:12570162)
• randomly unpredictable amino acid pairs are more sensitive to variants (PMID:12824704)
• the Pro55Ser mutation causes hemophilia primarily through to an impaired ability to activate FX whereas at least in vitro the Pro55Leu defect interferes with the activation of FIX. (PMID:12871416)
• the addition of the cytoplasmic domain of P-selectin to FIX modifies the cellular fate of the FIX molecule by directing the recombinant protein toward regulated-secretory granules without altering its coagulant activity (PMID:12871503)
• high levels of coagulation FXI, FIX and FVIII are related to risk of inherited thrombophilia syndrome (PMID:14521595)
• findings suggest that antithrombin exosites responsible for enhancing the rates of factor Xa and factor IXa inhibition in the conformationally activated inhibitor lie in strand 3 of beta-sheet C of the serpin (PMID:14532267)
• Review. The FXI gene is encodes a 607 AA zymogen for a serine protease. The serine protease domain is similar many other coagulation factors; the heavy chain contains 4 tandem Apple domains. FXI is a homodimer, which essential for normal function. (PMID:14567539)
• FIXa/FVIIIa binding studies of coordinate binding of FVIIIa and FX to equivalent numbers of binding sites on activated platelets provide strong evidence that FVIIIa comprises the receptor that presents FX to FIXa for catalysis on the platelet membrane. (PMID:14629468)
• binding of the factor IX gamma-carboxyglutamic acid domain to the vitamin K-dependent gamma-glutamyl carboxylase active site has a role in carboxylation and regulation of release of carboxylated product (PMID:14660587)
• complex structure shows that the complementarity determining region loops of the 10C12 antibody form a hydrophobic pocket to accommodate the hydrophobic patch of the Gla domain consisting of Leu-6, Phe-9, and Val-10. (PMID:14722079)
• IXabeta functions within the intrinsic Xase complex to activate X and may play a significant role in producing Xa necessary for the procoagulant response following vascular damage (PMID:14963035)
• FIX gene seems to be intact in the derivative 14, the breakpoint may affect an upstream regulatory sequence that subjects the gene to position effect variegation in hemophilia. (PMID:15009460)
• two common intragenic markers (TaqI and XmnI) in Iranian haemophilia B families (PMID:15183040)
• results strongly suggest that chaperone and lectin molecules act in concert to ensure both proper folding of FIXwt and the retention of mutant molecules (PMID:15219198)
• the antithrombin hinge region extension is the activating conformational change for inhibition of factors IXa and Xa (PMID:15326167)
• residues Asn89, Ile90, and Val107 within loops 1 and 2 (Cys88-Cys109) of the EGF2 domain of factor IXa are essential for normal interactions with the platelet surface and for the assembly of the factor X-activating complex on activated platelets (PMID:15328360)
• H-2 (and other) genes control factor IX antibody development in mice. (PMID:15383460)
• Glu555 alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa site and residues on F9 and antithrombin. FXI-Glu555 is the first reported FXI variant with a defect in FIX activation. (PMID:15456490)
• A proposed model of the interaction of factor IX peptide comprised of amino acids Gly4-Gln11 enables correlation of known hemophilia B mutations of factor IX at Lys5 or Phe9 with impaired phosphatidylserine interaction. (PMID:15581349)
• 2 new point mutations and a new deletion were found in hemophilia B families from northern India. (PMID:15590401)
• EGF-like domains of factor Xa and factor IXa are important for the activation of the factor VII–tissue factor complex (PMID:15634274)
• factor IX binds initially to exosites on the factor XIa heavy chain, followed by interaction at the active site with subsequent bond cleavage (PMID:15829482)
• analysis of missense mutations in two patients with factor XI deficiency (Val271Leu and Tyr351Ser) and one patient with combined factor XI and factor IX deficiency (Phe349Val)[letter] (PMID:15842381)
• analysis of factor IX(a) binding to Rhodnius nitrophorin 2 (PMID:15866866)
• in the presence of Ca2+, phospholipid, and factor VIIIa, binding of Na+ to factor IXa increases its biologic activity (PMID:15913649)
• Ten representative three-dimensional models of the FVIIIa-FIXa complex are presented based on agreements with known experimental data and according to structural criteria. (PMID:16102111)
• Therapeutic levels of human FIX were achieved in nonhuman primates using an adeno-associated virus as a vector for gene therapy of hemophilia B. (PMID:16322469)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	f9b	ENSDARG00000029493
mus_musculus	F9	ENSMUSG00000031138
rattus_norvegicus	F9	ENSRNOG00000003430

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Protein

Protein identifiers

Coagulation factor IX — P00740 (reviewed: P00740)

Alternative names: Christmas factor, Plasma thromboplastin component

All UniProt accessions (1): P00740

UniProt curated annotations — full annotation on UniProt →

Function. Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.

Subunit / interactions. Heterodimer of a light chain and a heavy chain; disulfide-linked. Interacts (inactive and activated) with F11 (activated) in calcium-dependent manner. Interacts with SERPINC1. Interacts (activated) with iripin-8, a serine protease inhibitor from Ixodes ricinus saliva. Interacts (inactive and activated) with nitrophorin-2, an anticoagulant protein from Rhodnius prolixus.

Subcellular location. Secreted.

Tissue specificity. Detected in blood plasma (at protein level). Synthesized primarily in the liver and secreted in plasma.

Post-translational modifications. Activated by factor XIa, which excises the activation peptide. The propeptide can also be removed by snake venom protease. Activated by coagulation factor VIIa-tissue factor (F7-F3) complex in calcium-dependent manner. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains. Predominantly O-glucosylated at Ser-99 by POGLUT1 in vitro. Carboxylated by vitamin K-dependent GGCX to form gamma-carboxyglutamate; these residues are essential for the binding of calcium.

Disease relevance. Hemophilia B (HEMB) [MIM:306900] An X-linked blood coagulation disorder characterized by a permanent tendency to hemorrhage, due to factor IX deficiency. It is phenotypically similar to hemophilia A, but patients present with fewer symptoms. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. The disease is caused by variants affecting the gene represented in this entry. Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide. Mutation in position 93 (Alabama) probably fails to bind to cell membranes. Mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya or Hilo) prevent cleavage of the activation peptide. Thrombophilia, X-linked, due to factor IX defect (THPH8) [MIM:300807] A hemostatic disorder characterized by a tendency to thrombosis. The disease is caused by variants affecting the gene represented in this entry. Warfarin sensitivity, X-linked (WARFS) [MIM:301052] A condition characterized by sensitivity to warfarin, a drugs used as anti-coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement. Warfarin sensitive individuals develop bleeding complications when they are given warfarin within the therapeutic ranges. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Calcium binds to the gamma-carboxyglutamic acid (Gla) residues in the Gla domain. Calcium can also bind, with stronger affinity, to another site beyond the Gla domain. Under physiological ion concentrations, Ca(2+) is displaced by Mg(2+) from some of the gammaglutamate residues in the N-terminal Gla domain. This leads to a subtle conformation change that may affect the interaction with its binding protein.

Miscellaneous. In 1952, one of the earliest researchers of the disease, Dr. R.G. Macfarlane used the patient’s surname, Christmas, to refer to the disease and also to refer to the clotting factor which he called the ‘Christmas Factor’. At the time, Stephen Christmas was a 5-year-old boy. He died in 1993 at the age of 46 from acquired immunodeficiency syndrome contracted through treatment with blood products.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P00740-1	1	yes
P00740-2	2

RefSeq proteins (2): NP_000124, NP_001300842 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000294	GLA_domain	Domain
IPR000742	EGF	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR012224	Pept_S1A_FX	Family
IPR017857	Coagulation_fac-like_Gla_dom	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR043504
IPR050442	Peptidase_S1_coag_factors	Family

Pfam: PF00008, PF00089, PF00594, PF14670

Enzyme classification (BRENDA):

• EC 3.4.21.22 — coagulation factor IXa (BRENDA: 3 organisms, 57 substrates, 216 inhibitors, 101 Km, 85 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FACTOR X	—	79
4-METHYLSULFONYL-D-LEU-GLY-ARG-P-NITROANILIDE	0.5–8.7	8
CH3SO2-D-LEU-GLY-ARG-4-NITROANILIDE	1.7–3.2	6
L-LEU-GLY-L-ARG-4-NITROANILIDE	1.2–2.3	2
CH3SO2-D-LEU-GLY-L-ARG-P-NITROANILIDE	2.3	1
METHOXYCARBONYL-D-NLE-GLY-ARG-P-NITROANILIDE	3.62	1
METHYLSULFONYL-D-CYCLOHEXYLGLYCYL-GLY-ARG-P-NITR	1.43	1
METHYLSULFONYL-D-HEXAHYDROTYROSYL-GLY-ARG-P-NITR	5.99	1

UniProt features (296 total): sequence variant 156, binding site 35, strand 32, modified residue 17, disulfide bond 11, helix 9, turn 8, glycosylation site 8, mutagenesis site 4, domain 4, active site 3, chain 3, propeptide 2, site 2, signal peptide 1, splice variant 1

Structure

Experimental structures (PDB)

56 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5JB9	X-RAY DIFFRACTION	1.3
6MV4	X-RAY DIFFRACTION	1.37
5JBA	X-RAY DIFFRACTION	1.4
5TNT	X-RAY DIFFRACTION	1.4
4YZU	X-RAY DIFFRACTION	1.41
4Z0K	X-RAY DIFFRACTION	1.41
5JB8	X-RAY DIFFRACTION	1.45
1EDM	X-RAY DIFFRACTION	1.5
2WPH	X-RAY DIFFRACTION	1.5
5TNO	X-RAY DIFFRACTION	1.54
5JBB	X-RAY DIFFRACTION	1.56
2WPJ	X-RAY DIFFRACTION	1.6
6RFK	X-RAY DIFFRACTION	1.6
4WMA	X-RAY DIFFRACTION	1.62
3KCG	X-RAY DIFFRACTION	1.7
2WPL	X-RAY DIFFRACTION	1.82
5EGM	X-RAY DIFFRACTION	1.84
4ZAE	X-RAY DIFFRACTION	1.86
4WMI	X-RAY DIFFRACTION	1.87
8EPH	X-RAY DIFFRACTION	1.88
3LC3	X-RAY DIFFRACTION	1.9
5F86	X-RAY DIFFRACTION	1.9
5JBC	X-RAY DIFFRACTION	1.9
4WN2	X-RAY DIFFRACTION	1.95
4WNH	X-RAY DIFFRACTION	1.95
2WPI	X-RAY DIFFRACTION	1.99
6X5P	X-RAY DIFFRACTION	2
2WPM	X-RAY DIFFRACTION	2
4WMB	X-RAY DIFFRACTION	2.05
4WMK	X-RAY DIFFRACTION	2.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00740-F1	80.45	0.51

Antibody-complex structures (SAbDab): 3 — 1NL0, 7AHV, 8OL9

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 267 (charge relay system); 315 (charge relay system); 411 (charge relay system); 191–192 (cleavage; by factor xia); 226–227 (cleavage; by factor xia)

Ligand- & substrate-binding residues (35): 47; 48; 53 (via 4-carboxyglutamate); 53 (via 4-carboxyglutamate); 54 (via 4-carboxyglutamate); 54 (via 4-carboxyglutamate); 61 (via 4-carboxyglutamate); 61 (via 4-carboxyglutamate); 63 (via 4-carboxyglutamate); 63 (via 4-carboxyglutamate); 63 (via 4-carboxyglutamate); 66 (via 4-carboxyglutamate) …

Post-translational modifications (17): 53, 54, 61, 63, 66, 67, 72, 73, 76, 79, 82, 86, 110, 114, 201, 204, 205

Disulfide bonds (11): 64–69, 97–108, 102–117, 119–128, 134–145, 141–155, 157–170, 178–335, 252–268, 382–396, 407–435

Glycosylation sites (8): 85, 99, 107, 203, 205, 213, 215, 225

Mutagenesis-validated functional residues (4):

Position	Phenotype
305	strongly increases enzyme activity with a synthetic peptide substrate; when associated with t-311; a-365 and t-391.
311	strongly increases enzyme activity with a synthetic peptide substrate; when associated with f-305; a-365 and t-391.
312	strongly decreases enzyme activity with a synthetic peptide substrate.
391	strongly increases enzyme activity with a synthetic peptide substrate; when associated with f-305; t-311 and a-365.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-159740	Gamma-carboxylation of protein precursors
R-HSA-159763	Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus
R-HSA-159782	Removal of aminoterminal propeptides from gamma-carboxylated proteins
R-HSA-9629569	Protein hydroxylation
R-HSA-9672383	Defective factor IX causes thrombophilia
R-HSA-9672396	Defective cofactor function of FVIIIa variant
R-HSA-9673202	Defective F9 variant does not activate FX
R-HSA-9673218	Defective F9 secretion
R-HSA-9673221	Defective F9 activation
R-HSA-9673240	Defective gamma-carboxylation of F9
R-HSA-9769735	Initiation of coagulation cascade
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9769743	Amplification and propagation of coagulation cascade
R-HSA-9935598	FXIIa, PKa-dependent activation of coagulation pathway
R-HSA-140834
R-HSA-140837

MSigDB gene sets: 182 (showing top): GOBP_PROTEIN_ACTIVATION_CASCADE, CEBPB_01, GOBP_WOUND_HEALING, GOBP_PROTEIN_MATURATION, REACTOME_GAMMA_CARBOXYLATION_TRANSPORT_AND_AMINO_TERMINAL_CLEAVAGE_OF_PROTEINS, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, HSIAO_LIVER_SPECIFIC_GENES, GOBP_BLOOD_COAGULATION_INTRINSIC_PATHWAY, CAIRO_HEPATOBLASTOMA_DN, BROWN_MYELOID_CELL_DEVELOPMENT_DN, TGGNNNNNNKCCAR_UNKNOWN, REACTOME_INTRINSIC_PATHWAY_OF_FIBRIN_CLOT_FORMATION, GOBP_HEMOSTASIS, BIOCARTA_INTRINSIC_PATHWAY, GOBP_REGULATION_OF_BODY_FLUID_LEVELS

GO Biological Process (4): proteolysis (GO:0006508), blood coagulation (GO:0007596), zymogen activation (GO:0031638), hemostasis (GO:0007599)

GO Molecular Function (8): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Defective factor IX causes hemophilia B	4
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
Coagulation pathway	3
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Defects of Coagulation cascade	1
Defective factor VIII causes hemophilia A	1
Regulation of clotting cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
intracellular organelle lumen	2
protein metabolic process	1
hemostasis	1
wound healing	1
coagulation	1
protein processing	1
regulation of body fluid levels	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
Golgi apparatus	1
membrane	1
cell periphery	1
external encapsulating structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1376 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
F9	F8	P00451	990
F9	F3	P13726	978
F9	F7	P08709	931
F9	GGCX	P38435	889
F9	SERPINC1	P01008	864
F9	VWF	P04275	838
F9	F2	P00734	808
F9	VKORC1	Q9BQB6	748
F9	KNG1	P01042	726
F9	ALB	P02768	680
F9	TFPI	P10646	675
F9	THBD	P07204	672
F9	ATP11C	Q8NB49	667
F9	IDS	P22304	647
F9	EGF	P01133	623

IntAct

11 interactions, top by confidence:

A	B	Type	Score
Xxylt1	F9	psi-mi:“MI:0559”(glycosylation reaction)	0.620
Xxylt1	F9	psi-mi:“MI:0407”(direct interaction)	0.620
F8	F9	psi-mi:“MI:0407”(direct interaction)	0.540
F8	F9	psi-mi:“MI:0915”(physical association)	0.540
F9	UBR5	psi-mi:“MI:0914”(association)	0.530
SERPINC1	F9	psi-mi:“MI:0407”(direct interaction)	0.440
F9	GAMMAHV.ORF33	psi-mi:“MI:0915”(physical association)	0.370
F9	DDX11L8	psi-mi:“MI:0914”(association)	0.350
F9	APBB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (64): FERMT2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), RBM14-RBM4 (Affinity Capture-MS), DCP2 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), FIGNL1 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), EOGT (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ZNHIT6 (Affinity Capture-MS), HELLS (Affinity Capture-MS), UBR5 (Affinity Capture-MS), YY1 (Affinity Capture-MS), TMEM55A (Affinity Capture-MS), POGLUT1 (Affinity Capture-MS)

ESM2 similar proteins: A0A126GUP6, A0A1S4H5M5, A0A1S4H5S2, A6MFK7, B5U2W0, F5HKX0, O60235, O88947, O97366, P00740, P05049, P13582, P15120, P15638, P16292, P16293, P16294, P19540, P21902, P25155, P29598, P49150, P81428, P82807, P83370, P98121, Q14C59, Q27081, Q27083, Q2VG86, Q3UQ41, Q49QW1, Q4QXT9, Q63207, Q6ZMR5, Q7PEV7, Q7QBP4, Q804X6, Q8I6K0, Q8MZM7

Diamond homologs: A0A1S4H5M5, A0A1S4H5S2, A0A6I8TBG6, A0A6J1W8N1, A6MFK7, A6MFK8, B8V7S0, F5HKX0, O18783, O19045, O88947, O97366, P00740, P00741, P00742, P00743, P00745, P00747, P00761, P03951, P06868, P08217, P12545, P14272, P15944, P16293, P16295, P19236, P19540, P20231, P21845, P26262, P27435, P31394, P33587, P35033, P35041, P50342, P50343, P56677

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
CEBPA	“up-regulates quantity by expression”	F9	“transcriptional regulation”
F9	“up-regulates activity”	F7	cleavage
F11	“up-regulates activity”	F9	cleavage
“Factor FVIIa:TF”	“up-regulates activity”	F9	binding
F7	“up-regulates activity”	F9	binding
GGCX	“up-regulates activity”	F9	carboxylation
F9	“form complex”	“Factor VIIIa-IXa”	binding
SERPINC1	“down-regulates activity”	F9	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

699 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	208
Likely pathogenic	102
Uncertain significance	130
Likely benign	179
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10558	NC_000023.11:g.139530716T>A	Pathogenic
10561	NM_000133.4(F9):c.-17del	Pathogenic
10565	NM_000133.4(F9):c.138G>Y (p.Arg46Ser)	Pathogenic
10566	E7D	Pathogenic
10567	NM_000133.4(F9):c.169C>T (p.Gln57Ter)	Pathogenic
10568	NM_000133.4(F9):c.52T>C (p.Cys18Arg)	Pathogenic
10571	NM_000133.4(F9):c.218A>T (p.Glu73Val)	Pathogenic
10572	NM_000133.4(F9):c.223C>T (p.Arg75Ter)	Pathogenic
10573	NM_000133.4(F9):c.224G>A (p.Arg75Gln)	Pathogenic
10574	NM_000133.4(F9):c.237A>C (p.Glu79Asp)	Pathogenic
10576	NM_000133.4(F9):c.278A>G (p.Asp93Gly)	Pathogenic
10578	NM_000133.4(F9):c.301C>G (p.Pro101Ala)	Pathogenic
10579	NM_000133.4(F9):c.316G>A (p.Gly106Ser)	Pathogenic
10580	NM_000133.4(F9):c.329A>G (p.Asp110Gly)	Pathogenic
10581	NM_000133.4(F9):c.479G>C (p.Gly160Ala)	Pathogenic
10582	NM_000133.4(F9):c.496A>T (p.Asn166Tyr)	Pathogenic
10585	NM_000133.4(F9):c.572G>A (p.Arg191His)	Pathogenic
10587	NM_000133.4(F9):c.880C>T (p.Arg294Ter)	Pathogenic
10589	NM_000133.4(F9):c.655C>T (p.Gln219Ter)	Pathogenic
10591	NM_000133.4(F9):c.677G>A (p.Arg226Gln)	Pathogenic
10592	NM_000133.4(F9):c.541G>T (p.Val181Phe)	Pathogenic
10593	NM_000133.4(F9):c.682G>T (p.Val228Phe)	Pathogenic
10594	NM_000133.4(F9):c.682G>C (p.Val228Leu)	Pathogenic
10595	NM_000133.4(F9):c.709C>T (p.Gln237Ter)	Pathogenic
10596	NM_000133.4(F9):c.710A>T (p.Gln237Leu)	Pathogenic
10597	NM_000133.4(F9):c.723+1G>T	Pathogenic
10598	F9, TRP215TER	Pathogenic
10601	NM_000133.4(F9):c.697G>A (p.Ala233Thr)	Pathogenic
10602	NM_000133.4(F9):c.881G>A (p.Arg294Gln)	Pathogenic
10603	NM_000133.4(F9):c.892C>T (p.Arg298Ter)	Pathogenic

SpliceAI

1076 predictions. Top by Δscore:

Variant	Effect	Δscore
X:139537004:TTTCA:T	acceptor_loss	1.0000
X:139537005:TTCAG:T	acceptor_loss	1.0000
X:139537006:TCAGT:T	acceptor_loss	1.0000
X:139537007:CAGTT:C	acceptor_loss	1.0000
X:139537008:A:AG	acceptor_gain	1.0000
X:139537009:G:GG	acceptor_gain	1.0000
X:139537009:GT:G	acceptor_gain	1.0000
X:139537009:GTT:G	acceptor_gain	1.0000
X:139537009:GTTT:G	acceptor_gain	1.0000
X:139537009:GTTTT:G	acceptor_gain	1.0000
X:139537169:GAACA:G	donor_gain	1.0000
X:139537171:ACA:A	donor_gain	1.0000
X:139537174:G:GG	donor_gain	1.0000
X:139551060:A:AG	acceptor_gain	1.0000
X:139551061:G:GG	acceptor_gain	1.0000
X:139551061:GTGCC:G	acceptor_gain	1.0000
X:139560740:GGTT:G	acceptor_gain	1.0000
X:139560851:CGCAG:C	donor_loss	1.0000
X:139560853:CAGG:C	donor_loss	1.0000
X:139560854:AGGT:A	donor_loss	1.0000
X:139560855:GGTA:G	donor_loss	1.0000
X:139560856:G:GC	donor_loss	1.0000
X:139560857:T:G	donor_loss	1.0000
X:139561520:ATAGG:A	acceptor_loss	1.0000
X:139561522:A:AG	acceptor_gain	1.0000
X:139561523:G:GC	acceptor_loss	1.0000
X:139561523:G:GG	acceptor_gain	1.0000
X:139561523:GGT:G	acceptor_gain	1.0000
X:139537003:A:AG	acceptor_gain	0.9900
X:139537004:T:G	acceptor_gain	0.9900

AlphaMissense

3048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:139561871:T:A	C396S	0.997
X:139561872:G:C	C396S	0.997
X:139561904:T:A	C407S	0.997
X:139561905:G:C	C407S	0.997
X:139541120:T:A	C108S	0.996
X:139541121:G:C	C108S	0.996
X:139561745:A:C	S354R	0.996
X:139561747:T:A	S354R	0.996
X:139561747:T:G	S354R	0.996
X:139561753:G:C	W356C	0.996
X:139561753:G:T	W356C	0.996
X:139561973:A:C	S430R	0.996
X:139561975:C:A	S430R	0.996
X:139561975:C:G	S430R	0.996
X:139537111:T:A	C64S	0.995
X:139537112:G:C	C64S	0.995
X:139537126:T:A	C69S	0.995
X:139537127:G:C	C69S	0.995
X:139561634:G:C	A317P	0.995
X:139561638:T:C	L318P	0.995
X:139561871:T:C	C396R	0.995
X:139561872:G:A	C396Y	0.995
X:139561873:T:G	C396W	0.995
X:139541087:T:A	C97S	0.994
X:139541088:G:C	C97S	0.994
X:139541102:T:A	C102S	0.994
X:139541103:G:C	C102S	0.994
X:139541180:T:A	C128S	0.994
X:139541181:G:C	C128S	0.994
X:139561829:T:A	C382S	0.994

dbSNP variants (sampled 300 via entrez): RS1000003315 (X:139557434 A>G), RS1000056840 (X:139543306 G>T), RS1000105370 (X:139547695 G>A), RS1000116864 (X:139529380 C>T), RS1000136135 (X:139548110 A>G), RS1000248017 (X:139538600 T>A), RS1000303177 (X:139529783 C>T), RS1000506740 (X:139549957 G>T), RS1000634036 (X:139531800 C>A), RS1000661246 (X:139538075 A>G), RS1000724190 (X:139538936 A>G), RS1000768135 (X:139549492 C>T), RS1000985848 (X:139540822 G>T), RS1001011838 (X:139538835 T>C), RS1001344119 (X:139539778 T>C)

Disease associations

OMIM: gene MIM:300746 | disease phenotypes: MIM:300807, MIM:306900, MIM:134500, MIM:306700, MIM:617468

GenCC curated gene-disease

Disease	Classification	Inheritance
hemophilia B	Strong	X-linked
thrombophilia, X-linked, due to factor 9 defect	Strong	X-linked
severe hemophilia B	Supportive	X-linked
moderately severe hemophilia B	Supportive	X-linked
mild hemophilia B	Supportive	X-linked
symptomatic form of hemophilia B in female carriers	Supportive	X-linked

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hemophilia B	Definitive	XL
thrombophilia, X-linked, due to factor 9 defect	Limited	XL

Mondo (9): thrombophilia, X-linked, due to factor 9 defect (MONDO:0010432), hemophilia B (MONDO:0010604), hemophilia B leyden (MONDO:0850054), hemophilia A (MONDO:0010602), arthrogryposis multiplex congenita (MONDO:0015168), moderately severe hemophilia B (MONDO:0015716), severe hemophilia B (MONDO:0015715), mild hemophilia B (MONDO:0015717), symptomatic form of hemophilia B in female carriers (MONDO:0015788)

Orphanet (5): Hemophilia B (Orphanet:98879), Hemophilia B Leyden (Orphanet:617930), Hemophilia A (Orphanet:98878), Arthrogryposis multiplex congenita (Orphanet:1037), Moderate hemophilia B (Orphanet:169796)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0001419	X-linked recessive inheritance
HP:0001934	Persistent bleeding after trauma
HP:0002239	Gastrointestinal hemorrhage
HP:0002248	Hematemesis
HP:0002249	Melena
HP:0002625	Deep venous thrombosis
HP:0002758	Osteoarthritis
HP:0003645	Prolonged partial thromboplastin time
HP:0005261	Joint hemorrhage
HP:0005542	Prolonged whole-blood clotting time
HP:0008151	Prolonged prothrombin time
HP:0011858	Reduced factor IX activity
HP:0033061	Increased factor IX activity
HP:0100724	Hypercoagulability

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009097_17	Venous thromboembolism	3.000000e-17

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006467	Hemophilia A	C15.378.100.100.500; C15.378.100.141.500; C15.378.463.500; C16.320.099.500
D002836	Hemophilia B	C15.378.100.100.510; C15.378.100.141.510; C15.378.463.510; C16.320.099.510; C16.320.322.235
C567581	Thrombophilia, X-Linked, Due To Factor Ix Defect (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2016 (SINGLE PROTEIN), CHEMBL2111424 (SELECTIVITY GROUP), CHEMBL4296076 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 676 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1095032	LETAXABAN	2	375
CHEMBL206335	RAZAXABAN	2	301

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 57 [PMID: 20121197]	Inhibition	8.7	pIC50
emicizumab	Binding	5.8	pKd

Binding affinities (BindingDB)

694 measured of 820 human assays (820 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.03 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.02,7]nonadeca-1(18),2(7),3,5,15(19),16-hexaen-5-yl]carbamate	KI	0.04 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one	KI	0.05 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-17-chloro-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate	KI	0.05 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.06 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(13R,17S)-17-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-6,13-dimethyl-12-oxo-7,11,19-triazatetracyclo[16.3.1.02,10.04,8]docosa-1(22),2(10),3,5,8,18,20-heptaene-5-carboxylic acid	KI	0.06 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-4,5-difluoro-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one	KI	0.07 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
2-[(2-methylpropan-2-yl)oxy]ethyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.08 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
2-hydroxyethyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.08 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-17-methoxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[5-chloro-2-(trifluoromethyl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10S,14S)-14-[4-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-propan-2-yl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(6-cyano-2-fluoro-3-methylphenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.1 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-ethynyl-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.1 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(2H-triazol-4-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.11 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[5-chloro-2-(difluoromethoxy)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.13 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.02,7]nonadeca-1(18),2(7),3,5,15(19),16-hexaen-5-yl]carbamate	KI	0.15 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(6-acetyl-3-chloro-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8-azatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.17 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10S,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-11-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.18 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10,17-dimethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate	KI	0.2 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-2(7),3,5-trien-5-yl]carbamate	KI	0.21 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-2-fluoro-6-methylphenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.23 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(6-acetyl-3-chloro-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-17-fluoro-10-methyl-9-oxo-8-azatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.23 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-bromo-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.27 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(14R,18S)-18-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-14-methyl-8,12,20-triazatetracyclo[17.3.1.02,11.04,9]tricosa-1(23),2,5,9,11,19,21-heptaene-7,13-dione	KI	0.31 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(6-bromo-2-fluoro-3-methylphenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.38 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8-azatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.42 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylic acid	KI	0.44 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
ethyl 2-[5-[[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]amino]-1,3,4-oxadiazol-2-yl]acetate	KI	0.45 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.46 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-5-(pyridin-3-ylamino)-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.47 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(7S)-7-[[2-chloro-4-(1-methyl-5-oxo-1,2,4-triazol-4-yl)benzoyl]amino]-7-(3-fluorophenyl)-2-methyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	IC50	0.509 nM	US-10351558: Factor IXa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxopyridazin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.55 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-5-amino-14-[4-(3-chloro-2,6-difluorophenyl)-2-oxo-1-pyridinyl]-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.56 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-2-oxo-1-pyridinyl]-10-methyl-5-(pyrimidin-2-ylamino)-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.56 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8-azatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.59 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(7S)-2-methyl-7-phenyl-7-[[4-(1,2,4-triazol-4-yl)benzoyl]amino]-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	IC50	0.596 nM	US-10351558: Factor IXa inhibitors
methyl N-[(10R,14S)-14-[4-(5-chloro-2-methylphenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.62 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(7S)-7-[[2-chloro-4-(3-methoxy-1,2,4-triazol-1-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	IC50	0.636 nM	US-10351558: Factor IXa inhibitors
(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-5-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)amino]-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.67 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-5-[[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]amino]-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.69 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(14R,18S)-18-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-14-methyl-8,12,20-triazatetracyclo[17.3.1.02,11.04,9]tricosa-1(23),2(11),3,9,19,21-hexaene-7,13-dione	KI	0.72 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(7S)-7-[[2-chloro-4-(3-methyl-1,2,4-triazol-1-yl)benzoyl]amino]-7-(3-fluorophenyl)-2-methyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	IC50	0.791 nM	US-10351558: Factor IXa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-3-methyl-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.8 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-5-(pyridazin-3-ylamino)-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one	KI	0.8 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8-azatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylic acid	KI	0.81 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(E)-3-[(7S)-7-[[2-chloro-4-(1,2,4-triazol-4-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl]prop-2-enoic acid	IC50	0.82 nM	US-10351558: Factor IXa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10,17-dimethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate	KI	0.84 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.87 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors

ChEMBL bioactivities

940 potent at pChembl≥5 of 976 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	Ki	0.03	nM	CHEMBL4107149
10.40	Ki	0.04	nM	CHEMBL4110926
10.30	Ki	0.05	nM	CHEMBL4112773
10.30	Ki	0.05	nM	CHEMBL4114881
10.22	Ki	0.06	nM	CHEMBL4113483
10.22	Ki	0.06	nM	CHEMBL4109568
10.15	Ki	0.07	nM	CHEMBL4108033
10.10	Ki	0.08	nM	CHEMBL4115630
10.10	Ki	0.08	nM	CHEMBL4110983
10.05	Ki	0.09	nM	CHEMBL4111429
10.05	Ki	0.09	nM	CHEMBL4106708
10.05	Ki	0.09	nM	CHEMBL3948120
10.05	Ki	0.09	nM	CHEMBL4113824
10.00	Ki	0.1	nM	CHEMBL4114933
10.00	Ki	0.1	nM	CHEMBL4107808
9.96	Ki	0.11	nM	CHEMBL4115423
9.89	Ki	0.13	nM	CHEMBL4110346
9.82	Ki	0.15	nM	CHEMBL4110901
9.77	Ki	0.17	nM	CHEMBL4107795
9.74	Ki	0.18	nM	CHEMBL4115353
9.70	Ki	0.2	nM	CHEMBL4112648
9.68	Ki	0.21	nM	CHEMBL4114611
9.64	Ki	0.23	nM	CHEMBL4114880
9.64	Ki	0.23	nM	CHEMBL4112546
9.57	Ki	0.27	nM	CHEMBL4112357
9.51	Ki	0.31	nM	CHEMBL4109665
9.42	Ki	0.38	nM	CHEMBL4111371
9.38	Ki	0.42	nM	CHEMBL4112342
9.36	Ki	0.44	nM	CHEMBL4106934
9.35	Ki	0.45	nM	CHEMBL4107368
9.34	Ki	0.46	nM	CHEMBL4112597
9.33	Ki	0.47	nM	CHEMBL4111663
9.29	IC50	0.509	nM	CHEMBL5915125
9.26	Ki	0.55	nM	CHEMBL4109580
9.25	Ki	0.56	nM	CHEMBL4112483
9.25	Ki	0.56	nM	CHEMBL4111142
9.23	Ki	0.59	nM	CHEMBL4111308
9.22	Ki	0.6	nM	CHEMBL3629111
9.22	Ki	0.6	nM	CHEMBL3629114
9.22	IC50	0.596	nM	CHEMBL5780078
9.21	Ki	0.62	nM	CHEMBL4113149
9.20	IC50	0.636	nM	CHEMBL5743170
9.17	Ki	0.67	nM	CHEMBL4114332
9.16	Ki	0.69	nM	CHEMBL4115130
9.14	Ki	0.72	nM	CHEMBL4114872
9.10	Ki	0.8	nM	CHEMBL3628964
9.10	Ki	0.8	nM	CHEMBL4112921
9.10	Ki	0.8	nM	CHEMBL4113427
9.10	IC50	0.791	nM	CHEMBL5782236
9.09	Ki	0.81	nM	CHEMBL4113230

PubChem BioAssay actives

393 with measured affinity, of 702 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(7S)-7-[[2-chloro-4-(1,2,4-triazol-4-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0006	uM
(7S)-7-[[2,6-dichloro-4-(3-methyl-1,2,4-triazol-1-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0006	uM
(E)-3-[(7S)-7-[[2,6-dichloro-4-(1,2,4-triazol-4-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl]prop-2-enoic acid	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0008	uM
2,6-dichloro-N-[(2R)-2-(8-fluoro-5-methyl-4-oxo-3H-quinazolin-2-yl)-2-(3-fluorophenyl)ethyl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0010	uM
(7S)-7-[[2,6-dichloro-4-(1,2,4-triazol-4-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0012	uM
N-[(7S)-10-(5-amino-3-pyridinyl)-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-7-yl]-2,6-dichloro-4-(1,2,4-triazol-4-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0016	uM
2,6-dichloro-N-[(2R)-8-methyl-2-(3-methylphenyl)-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0018	uM
2,6-dichloro-N-[(2R)-2-(3-fluoro-4-hydroxyphenyl)-2-(2-methyl-3H-benzimidazol-5-yl)ethyl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1283907: Inhibition of human factor 9a using CH3SO2-DCHG-Gly-Arg-AFC.AcOH as substrate preinubated for 30 mins followed by substrate addition measured after 1 hr by fluorescence assay	ic50	0.0019	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[2-[(2-methylpropylamino)methyl]phenyl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0020	uM
2-chloro-N-[(2R)-8-methyl-2-(3-methylphenyl)-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0021	uM
2,6-dichloro-N-[(7S)-10-[(E)-hydroxyiminomethyl]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-7-yl]-4-(1,2,4-triazol-4-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0024	uM
2,6-dichloro-N-[(7S)-2-methyl-7-phenyl-10-(2H-tetrazol-5-yl)-8,9-dihydro-6H-pyrido[1,2-a]indol-7-yl]-4-(1,2,4-triazol-4-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0024	uM
(7S)-7-[[3-chloro-5-(1,2,4-triazol-4-yl)pyridine-2-carbonyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxylic acid	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0025	uM
(7S)-7-[[2-chloro-4-(1,2,4-triazol-4-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indole-10-carboxamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0026	uM
3-[(7S)-7-[[2-chloro-4-(3-methyl-1,2,4-triazol-1-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl]propanoic acid	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0027	uM
2,6-dichloro-N-[(2R)-2-(6-chloro-5-methoxy-1H-benzimidazol-2-yl)-2-(3-fluorophenyl)ethyl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0029	uM
2-[(7S)-7-[[2,6-dichloro-4-(1,2,4-triazol-4-yl)benzoyl]amino]-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl]acetic acid	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0029	uM
2-chloro-N-[(2R)-2-(3-methoxyphenyl)-8-methyl-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0030	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[2-(piperazin-1-ylmethyl)phenyl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0030	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[1,3-dimethyl-5-[(propan-2-ylamino)methyl]pyrazol-4-yl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0030	uM
methyl 2-[3-(2-carbamimidoyl-1-benzothiophen-5-yl)phenoxy]-2-thiophen-2-ylacetate	459575: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0030	uM
[(2R)-2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-(4-methoxyphenyl)carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0030	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[2-(methylaminomethyl)phenyl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0030	uM
2,6-dichloro-N-[(2R)-2-(3-chlorophenyl)-8-methyl-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0031	uM
2,6-dichloro-N-[(2R)-2-(8-fluoro-5-methyl-4-oxo-1H-quinolin-2-yl)-2-(3-fluorophenyl)ethyl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0033	uM
1-[3-chloro-4-[(10-hydroxy-2,7-dimethyl-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl)carbamoyl]phenyl]benzimidazole-5-carboxylic acid	1393328: Inhibition of recombinant human factor 9a	ki	0.0035	uM
2,6-dichloro-N-[(2R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(1,2,4-triazol-4-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0036	uM
2,6-dichloro-N-[(2S)-2-(3-fluorophenyl)-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0037	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[2-(aminomethyl)phenyl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0040	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[4-[2-(dimethylamino)ethoxy]phenyl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0040	uM
2,6-dichloro-N-[(2R)-2-(4-fluorophenyl)-8-methyl-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0042	uM
1-(3-carbamimidoylphenyl)-N-[4-(5-chlorobenzimidazol-1-yl)-2-fluorophenyl]-3-(trifluoromethyl)pyrazole-5-carboxamide	1796940: Enzyme Assay and Determination of the Inhibition Constants. from Article 10.1016/j.bmcl.2004.08.034: “SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa.”	ki	0.0042	uM
[2-[(2-carbamimidoyl-6-fluoro-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[2-(aminomethyl)phenyl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0044	uM
2,6-dichloro-4-(3-methyl-1,2,4-triazol-1-yl)-N-[(2R)-8-methyl-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0045	uM
2-chloro-N-[(1R,4S,7S)-2-(4-chloro-[1,2]oxazolo[5,4-c]pyridin-7-yl)-2-azabicyclo[2.2.1]heptan-7-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1450166: Inhibition of human coagulation factor 9a using SPECTROFLUOR F9a as substrate after 60 mins by fluorescence assay	ic50	0.0049	uM
2,6-dichloro-N-[(2R)-8-methyl-2-(1-propan-2-yltriazol-4-yl)-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0050	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[1-methyl-3-(methylaminomethyl)pyrazol-5-yl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0050	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-[1,3-dimethyl-5-(methylaminomethyl)pyrazol-4-yl]carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0050	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-(2-fluorophenyl)carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0050	uM
[2-[(2-carbamimidoyl-1-benzothiophen-4-yl)oxy]-2-phenylethyl] N-(4-methoxyphenyl)carbamate	459562: Inhibition of human recombinant factor 9a by amidolytic assay	ki	0.0050	uM
2,6-dichloro-N-[(7S)-10-cyano-2-methyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-7-yl]-4-(1,2,4-triazol-4-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0051	uM
1-(3-carbamimidoylphenyl)-N-[4-(6-chlorobenzimidazol-1-yl)-2-fluorophenyl]-3-(trifluoromethyl)pyrazole-5-carboxamide	1796940: Enzyme Assay and Determination of the Inhibition Constants. from Article 10.1016/j.bmcl.2004.08.034: “SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa.”	ki	0.0051	uM
2,6-dichloro-N-[(7S)-2-methyl-7-phenyl-10-(2,2,2-trifluoro-1-hydroxyethyl)-8,9-dihydro-6H-pyrido[1,2-a]indol-7-yl]-4-(1,2,4-triazol-4-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0055	uM
N-[4-(benzimidazol-1-yl)phenyl]-1-(3-carbamimidoylphenyl)-3-pyridin-3-ylpyrazole-5-carboxamide	1796940: Enzyme Assay and Determination of the Inhibition Constants. from Article 10.1016/j.bmcl.2004.08.034: “SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa.”	ki	0.0055	uM
2-chloro-N-[(2R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-(3-fluorophenyl)ethyl]-4-(1,2,4-triazol-4-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0057	uM
2-chloro-N-[(2S)-7-methyl-2-phenyl-3,4-dihydro-1H-pyrido[1,2-a]benzimidazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0059	uM
2,6-dichloro-N-[(2R)-2-(6-chloro-4-methyl-1H-benzimidazol-2-yl)-2-(3-fluorophenyl)ethyl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252147: Inhibition of human coagulation factor 9a using fluorescent peptide CH3SO2-D-CHG-Gly-Arg-AFC-AcoH as substrate	ki	0.0062	uM
2,6-dichloro-N-[(7S)-2,10-dimethyl-7-phenyl-8,9-dihydro-6H-pyrido[1,2-a]indol-7-yl]-4-(1,2,4-triazol-4-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0063	uM
1-(3-carbamimidoylphenyl)-N-[2-fluoro-4-[5-(trifluoromethyl)benzimidazol-1-yl]phenyl]-3-(trifluoromethyl)pyrazole-5-carboxamide	1796940: Enzyme Assay and Determination of the Inhibition Constants. from Article 10.1016/j.bmcl.2004.08.034: “SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa.”	ki	0.0064	uM
2,6-dichloro-N-[(2R)-2-(3-fluorophenyl)-8-methyl-3,4-dihydro-1H-pyrido[1,2-b]indazol-2-yl]-4-(3-methyl-1,2,4-triazol-1-yl)benzamide	1252501: Inhibition of human F9a using CH3SO2-D-CHG-Gly-Arg-AFC.AcOH as substrate by fluorescence assay	ki	0.0066	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
methyleugenol	decreases expression	1
bisphenol A	decreases expression	1
vitamin K1 oxide	increases activity, increases carboxylation, increases reduction	1
sodium arsenite	decreases expression	1
coumarin	increases response to substance	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
RB 006	decreases activity, decreases reaction, affects binding	1
RB 007	affects binding, decreases activity, decreases reaction	1
Acetaminophen	decreases expression	1
Betaine	increases secretion	1
Calcium Chloride	increases activity, affects cotreatment	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Cholic Acids	affects cotreatment, affects expression	1
Contraceptives, Oral	increases expression	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Gentamicins	increases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	1
Glycocholic Acid	affects cotreatment, decreases expression	1
Glycodeoxycholic Acid	affects cotreatment, decreases expression	1
Methyltestosterone	affects cotreatment, affects expression	1
N-Nitrosopyrrolidine	decreases expression	1
Vitamin K 1	increases carboxylation, increases reduction, increases activity	1
Tamoxifen	increases expression	1
Tartrazine	affects cotreatment, decreases expression	1
Valproic Acid	decreases expression	1
Warfarin	increases response to substance	1

ChEMBL screening assays

108 unique, capped per target: 107 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005616	Binding	Inhibition of human factor 9a	Factor VIIa inhibitors: target hopping in the serine protease family using X-ray structure determination. — Bioorg Med Chem Lett
CHEMBL4621402	ADMET	Inhibition of human F9a using fluorescent peptide as substrate by florescence assay	Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach. — J Med Chem

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 2 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_AU00	293T-FIX	Transformed cell line	Female
CVCL_AU01	SK-HEP-1-FIX	Cancer cell line	Male
CVCL_B3RZ	SXMUi001-A	Induced pluripotent stem cell	Male
CVCL_B6DP	TMhep39	Cancer cell line
CVCL_B6DQ	TMhep48	Cancer cell line
CVCL_E4JT	CHO FIX.1F	Transformed cell line	Female
CVCL_XG90	HT-1080 JH-1/FIX	Cancer cell line	Male

Clinical trials (associated diseases)

172 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00139828	PHASE4	COMPLETED	Post Marketing Study in Haemophilia B Patients Using Nonafact® (Human Coagulation Factor IX)
NCT00581126	PHASE4	COMPLETED	Study Evaluating BENEFIX in Previously Treated Patients With Hemophilia B
NCT00749476	PHASE4	COMPLETED	Study Evaluating BeneFIX in Patients With Haemophilia B, Previously Treated With Plasma Derived Factor IX
NCT01128881	PHASE4	COMPLETED	IMMUNINE Pre-Treatment Study
NCT01748201	PHASE4	COMPLETED	Viscosupplementation in Patients With Hemophilic Arthropathy
NCT02336178	PHASE4	COMPLETED	Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China
NCT03565237	PHASE4	COMPLETED	RIXUBIS PMS India (RIXUBIS PMS)
NCT04286412	PHASE4	COMPLETED	Nonacog Alfa Prophylaxis And Treatment Of Bleeding Episodes In Previously Treated Patients With Hemophilia B
NCT05856266	PHASE4	TERMINATED	An 18-month Low-interventional Study to Assess Joint Health in Haemophilia A and B Patients on Prophylaxis With Efmoroctocog Alfa or Eftrenonacog Alfa
NCT00037557	PHASE3	COMPLETED	Study Evaluating rFIX; BeneFIX in Severe Hemophilia B
NCT00093171	PHASE3	COMPLETED	Study Evaluating rFIX; BeneFIX® in Hemophilia B
NCT00093210	PHASE3	COMPLETED	Study Evaluating of Recombinant Human Factor IX (BeneFIX) and a New Formulation of BeneFIX (rFIX-R) in Moderate to Severe Hemophilia B
NCT00364182	PHASE3	COMPLETED	Study Comparing On-Demand Treatment With Two Prophylaxis Regimens Of BeneFIX In Patients With Severe Hemophilia B
NCT00851721	PHASE3	COMPLETED	Efficacy and Safety Study of Prophylactic Versus On-Demand Treatment With Feiba NF in Subjects With Hemophilia A or B and a High Titer Inhibitor
NCT00866606	PHASE3	COMPLETED	Study Evaluating On-Demand Treatment With BeneFIX In Chinese Subjects
NCT01174446	PHASE3	COMPLETED	Pivotal Study (Pharmacokinetics, Efficacy, Safety) of BAX 326 (rFIX) in Hemophilia B Patients
NCT01271868	PHASE3	TERMINATED	Study of Recombinant Factor IX Product, IB1001, in Previously Treated Pediatric Subjects With Hemophilia B
NCT01286779	PHASE3	COMPLETED	BAX 326 (rFIX) Continuation Study
NCT01335061	PHASE3	COMPLETED	Study To Compare On-Demand Treatment To A Prophylaxis Regimen Of BeneFIX In Subjects With Moderately Severe to Severe Hemophilia B
NCT01440946	PHASE3	COMPLETED	Study of Recombinant Coagulation Factor IX Fc Fusion Protein, BIIB029, in Previously Treated Pediatric Participants With Hemophilia B
NCT01507896	PHASE3	COMPLETED	BAX 326 Surgery Study in Hemophilia B Patients
NCT01662531	PHASE3	COMPLETED	A Safety, Efficacy and Pharmacokinetics Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Children With Hemophilia B
NCT01757405	PHASE3	COMPLETED	Recombinant Factor VIIa BI (rFVIIa BI) Treatment of Acute Bleeding Episodes Per an On-demand Regimen
NCT02048111	PHASE3	WITHDRAWN	Study of Recombinant Factor IX Product, IB1001, in Previously Treated Subjects With Hemophilia B
NCT02053792	PHASE3	COMPLETED	A Safety and Efficacy Extension Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B
NCT02234310	PHASE3	COMPLETED	Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B
NCT03417102	PHASE3	COMPLETED	A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors
NCT03417245	PHASE3	COMPLETED	A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors
NCT03569891	PHASE3	COMPLETED	HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients
NCT03587116	PHASE3	COMPLETED	A Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FVIII:C≤1%)
NCT03855280	PHASE3	COMPLETED	Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B
NCT03861273	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B
NCT03938792	PHASE3	COMPLETED	Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Participants With Severe Hemophilia A or Moderately Severe to Severe Hemophilia B
NCT05145127	PHASE3	RECRUITING	Open-Label Extension Study of Marstacimab in Hemophilia Participants With or Without Inhibitors
NCT05487976	PHASE3	UNKNOWN	Clinical Study of Recombinant Human Activated Coagulation Factor VII for Injection in Patients With Hemophilia With Inhibitor
NCT05568719	PHASE3	RECRUITING	Safety and Effectiveness of Giroctocogene Fitelparvovec or Fidanacogene Elaparvovec in Patients With Hemophilia A or B Respectively
NCT05611801	PHASE3	RECRUITING	A Clinical Trial of Study Medicine (Marstacimab) in Pediatric Patients With Hemophilia A or Hemophilia B
NCT06003387	PHASE3	RECRUITING	Efficacy and Safety of CSL222 (Etranacogene Dezaparvovec) Gene Therapy in Adults With Hemophilia B With Pretreatment Adeno-associated Virus Serotype 5 (AAV5) Neutralizing Antibodies (Nabs)
NCT06399289	PHASE3	ACTIVE_NOT_RECRUITING	Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Chinese Subjects With Hemophilia B Previously Treated With FIX Therapy
NCT06568302	PHASE3	TERMINATED	The Long-term Safety and Efficacy of SerpinPC in Subjects with Hemophilia Who Completed a Sponsored SerpinPC Clinical Trial