ACVRL1

Summary

ACVRL1 (activin A receptor like type 1, HGNC:175) is a protein-coding gene on chromosome 12q13.13, encoding Activin receptor type-1-like (P37023). Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2.

Source: NCBI Gene 94 — RefSeq curated summary.

At a glance

• Gene–disease (curated): telangiectasia, hereditary hemorrhagic, type 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 1,250 total — 371 pathogenic, 130 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000020

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:175
Approved symbol	ACVRL1
Name	activin A receptor like type 1
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	HHT2, ALK1, HHT
Ensembl gene	ENSG00000139567
Ensembl biotype	protein_coding
OMIM	601284
Entrez	94

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000388922, ENST00000419526, ENST00000547400, ENST00000547632, ENST00000550084, ENST00000550683, ENST00000551576, ENST00000552678, ENST00000713618, ENST00000713619, ENST00000910197, ENST00000910198, ENST00000910199, ENST00000910200, ENST00000910201, ENST00000910202, ENST00000910203, ENST00000910204, ENST00000910205, ENST00000942784, ENST00000942785, ENST00000942786, ENST00000942787

RefSeq mRNA: 11 — MANE Select: NM_000020 NM_000020, NM_001077401, NM_001406487, NM_001406488, NM_001406489, NM_001406490, NM_001406491, NM_001406492, NM_001406493, NM_001406494, NM_001406495

CCDS: CCDS31804

Canonical transcript exons

ENST00000388922 — 10 exons

Exon	Start	End
ENSE00002284311	51913099	51913350
ENSE00002608385	51912470	51912535
ENSE00004011306	51913974	51914073
ENSE00004011307	51913559	51913770
ENSE00004011308	51916036	51916233
ENSE00004011310	51918985	51919115
ENSE00004011311	51920759	51923361
ENSE00004011312	51914439	51914585
ENSE00004011313	51915225	51915500
ENSE00004020484	51907504	51907695

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.15.

FANTOM5 (CAGE): breadth broad, TPM avg 6.3887 / max 222.2289, expressed in 773 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125526	2.9708	505
125530	1.9510	502
125531	0.5560	285
125528	0.4874	209
125532	0.1421	69
125533	0.1083	62
125527	0.1075	59
125529	0.0656	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	97.15	gold quality
upper lobe of left lung	UBERON:0008952	97.03	gold quality
upper lobe of lung	UBERON:0008948	96.85	gold quality
tendon of biceps brachii	UBERON:0008188	96.84	gold quality
apex of heart	UBERON:0002098	94.83	gold quality
mucosa of transverse colon	UBERON:0004991	93.67	gold quality
omental fat pad	UBERON:0010414	93.51	gold quality
peritoneum	UBERON:0002358	93.43	gold quality
left uterine tube	UBERON:0001303	92.78	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.73	gold quality
lower lobe of lung	UBERON:0008949	92.72	gold quality
transverse colon	UBERON:0001157	91.64	gold quality
lung	UBERON:0002048	91.56	gold quality
right lobe of thyroid gland	UBERON:0001119	91.15	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.05	gold quality
endocervix	UBERON:0000458	90.72	gold quality
rectum	UBERON:0001052	90.55	gold quality
metanephros cortex	UBERON:0010533	90.24	gold quality
colonic mucosa	UBERON:0000317	90.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.47	gold quality
lower esophagus	UBERON:0013473	89.39	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.38	gold quality
left lobe of thyroid gland	UBERON:0001120	89.14	gold quality
body of uterus	UBERON:0009853	88.99	gold quality
adipose tissue	UBERON:0001013	88.93	gold quality
ectocervix	UBERON:0012249	88.84	gold quality
heart left ventricle	UBERON:0002084	88.75	gold quality
mucosa of stomach	UBERON:0001199	88.72	gold quality
colon	UBERON:0001155	88.61	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	40.32
E-MTAB-8410	yes	25.70
E-GEOD-125970	yes	14.60
E-ANND-3	yes	13.21
E-MTAB-6701	yes	12.35
E-MTAB-5061	yes	5.92

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
BMPR2	Activation
CD34	Repression
EFNB2	Activation
ENG	Activation
ID1	Activation
ID2	Activation
TGFBR1	Activation

Upstream regulators (CollecTRI, top): KLF6, SMAD1, SP1, TCF7L2

miRNA regulators (miRDB)

110 targeting ACVRL1, 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-3613-3P	100.00	76.36	7965
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-4692	100.00	67.32	2066
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3175	99.65	66.30	2031

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. (PMID:12114496)
• signaling regulated by the nuclear receptor LXRbeta (PMID:12393874)
• 7 angiogenesis-related genes were found among 13 genes significantly induced or suppressed by a constitutively active ALK-1. ALK-1 is implicated in the maturation phase of angiogenesis. (PMID:12453878)
• A questionnaire based study provides evidence that the hereditary hemorrhagic telangiectasia (HHT) phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). (PMID:12920067)
• ALK5 mediates a TGFbeta-dependent recruitment of ALK1 into a TGFbeta receptor complex; ALK5 kinase activity is required for optimal ALK1 activation. (PMID:14580334)
• missense mutations of ALK-1 cause pulmonary hypertension in patients with hereditary haemorrhagic telangiectasia. (PMID:14684682)
• Mutational analysis of the ACVRL1 gene in hereditary hemorrhagic telangiectasia patients. (PMID:15024723)
• Mutation found in 40% of hereditary hemorrhagic telangiectasia patients. (PMID:15517393)
• retroviral gag- and gag-pol-like proteins interact with ALK1 (PMID:15611116)
• The ALK-1 mutant R484Q within the highly conserved NANDOR box region was found in an infant with idiopathic pulmonary arterial hypertension. (PMID:15687131)
• 5 new mutations were found in hereditary hemorrhagic telangiectasia: c.149G>A, c.246delC, c.1273T>G, c.1274_1276delTCT, and c.1377+1G>A. (PMID:15712270)
• 11 of 16 mutations in the ALK1 gene were novel single base pair substitutions in exons 4, 7, 8, & 9. The 1st de novo ALK1 mutation found causes a previously unreported c.1133C>A substitution of a highly conserved residue (p.P378H). (PMID:15712271)
• These results demonstrate the importance of ACVRL1 and ENG mutations in German hereditary hemorrhagic telangiectasia (HHT) patients displaying mutation frequencies over 80%. (PMID:15880681)
• HHT is an angiogenic disorder characterized by an over-expression of VEGF, TGF-beta1 and ALK1 (PMID:15951295)
• a polymorphism in ALK1 but not a polymorphism in ENG may have a role in development of sporadic brain arteriovenous malformations (PMID:16179574)
• ENG and ALK-1 genes may have roles in hereditary haemorrhagic telangiectasia in the Italian population (PMID:16429404)
• expression analysis of Endoglin and ALK1 in Spanish patients with hereditary hemorrhagic telangiectasia (PMID:16470589)
• Results showed 12 novel mutations in ACVRL1 gene causing hereditary hemorrhagic teleangiectasia. (PMID:16525724)
• Molecular analysis identified mutations in the ACVRL1 gene in patients affected with hereditary hemorrhagic telengiectasia. (PMID:16540754)
• An analysis of the genotype-phenotype correlation is consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in patients with ACVRL1 mutations in our collective. (PMID:16542389)
• The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs. (PMID:16776339)
• ALK1 is a preferred TGFbeta receptor kinase for endoglin threonine phosphorylation in HUVECs and endoglin phosphorylation has a role in the regulation of endothelial cell adhesion and growth by ALK1 (PMID:16785228)
• mutation causes truncation of the ALK-1 protein at the post-transcriptional level; the plasma thrombomodulin may provide an easy diagnostic indicator in HHT patients (PMID:16861286)
• The presence of mutations in the ALK-1 gene in ten patients with underlying connective tissue diseases was investigated (PMID:16941203)
• Bone Morphogenetic Protein 9 (BMP9) and BMP10 are two specific ALK1 ligands (PMID:17068149)
• These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. (PMID:17219009)
• Mutations in ACVRL1 gene is associated with symptomatic lung involvement and cerebral abscesses in hereditary hemorrhagic telangiectasia (PMID:17224686)
• These results suggest that BMP-9 is a physiological ALK1 ligand that plays an important role in the regulation of angiogenesis. (PMID:17311849)
• identification of a mutated ENG (HHT1) or ALK-1 (HHT2) gene now enables a genotype-phenotype correlation (PMID:17388964)
• These results support a significant role for ALK1 as a negative regulator of endothelial cell migration and suggest the implication of JNK and ERK as mediators of this effect. (PMID:17620321)
• Mutation analysis in ENG and ACVRL1 genes was performed in hereditary hemorrhagic telangiectasia patients. (PMID:17786384)
• Caveolin-1 interacts and cooperates with the transforming growth factor-beta type I receptor ALK1 in endothelial caveolae. (PMID:18065769)
• ALK1 plays as notable a role as BMPR2 in the etiology of PAH. Asymptomatic carriers with the ALK1 mutation within the serine - threonine kinase domain are at risk of developing PAH and hereditary hemorrhagic telangiectasia (PMID:18159113)
• reports haplotype analyis of 13 ACVRL1 mutations, which have been found in patients from France and Italy. One specific mutation (c.1112dupG) is repsonsible for the high frequence in Ain and Jura areas (PMID:18285823)
• BMP9 is indeed the ALK1 ligand present in human serum (PMID:18309101)
• 4 large novel deletions in ALK1 gene in a group of 45 clinically confirmed hereditary haemorrhagic telangiectasia families. 2 families, the whole ALK1 gene was deleted. 1 spanned at least 216 kb & included LOC728503, ANKRD33, ACVR1B, GRASP, & NR4A1 (PMID:18312453)
• both ALK1 and ALK5 are needed for TGF-beta-induced phosphorylation of intracellular mediators Smad1/5, whereas only ALK5 is essential for TGF-beta1-induced phosphorylation of Smad3 (PMID:18333754)
• identified ACVRL1 mutations in hereditary hemorrhagic telangiectasia, including 4 unknown, and found that ACVRL1, and not ENG, mutations are predictive for liver disease (PMID:18498373)
• The hereditary hemorrhagic telangiectasia family is caused by a 145delG mutation of ACVRL1 gene, resulting in frameshift and a new stop codon at codon 53. (PMID:18543223)
• in hereditary hemorrhagic telangiectasia all 4 ENG mutations and one of the ACVRL1 mutations were new and had not been described previously in other populations (PMID:18607909)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	acvr1l	ENSDARG00000014986
danio_rerio	acvrl1	ENSDARG00000018179
mus_musculus	Acvrl1	ENSMUSG00000000530
rattus_norvegicus	Acvrl1	ENSRNOG00000028713
drosophila_melanogaster	put	FBGN0003169
drosophila_melanogaster	sax	FBGN0003317
drosophila_melanogaster	tkv	FBGN0003716
drosophila_melanogaster	babo	FBGN0011300
drosophila_melanogaster	wit	FBGN0024179
caenorhabditis_elegans		WBGENE00000897
caenorhabditis_elegans		WBGENE00000900
caenorhabditis_elegans		WBGENE00004860

Paralogs (11): TGFBR1 (ENSG00000106799), BMPR1A (ENSG00000107779), ACVR2B (ENSG00000114739), ACVR1 (ENSG00000115170), ACVR2A (ENSG00000121989), ACVR1C (ENSG00000123612), AMHR2 (ENSG00000135409), ACVR1B (ENSG00000135503), BMPR1B (ENSG00000138696), TGFBR2 (ENSG00000163513), BMPR2 (ENSG00000204217)

Protein

Protein identifiers

Activin receptor type-1-like — P37023 (reviewed: P37023)

Alternative names: Activin receptor-like kinase 1, Serine/threonine-protein kinase receptor R3, TGF-B superfamily receptor type I

All UniProt accessions (10): P37023, A0A0S2Z2Y4, A0A0S2Z310, A0AAQ5BGI2, A0AAQ5BGI4, D9IPD9, E7EN07, F8W0N2, G3V1W8, H3BTZ2

UniProt curated annotations — full annotation on UniProt →

Function. Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well.

Subunit / interactions. Interacts with TSC22D1/TSC-22.

Subcellular location. Cell membrane.

Disease relevance. Telangiectasia, hereditary hemorrhagic, 2 (HHT2) [MIM:600376] A multisystemic vascular dysplasia leading to dilation of permanent blood vessels and arteriovenous malformations of skin, mucosa, and viscera. The disease is characterized by recurrent epistaxis and gastro-intestinal hemorrhage. Visceral involvement includes arteriovenous malformations of the lung, liver, and brain. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.

RefSeq proteins (11): NP_000011, NP_001070869, NP_001393416, NP_001393417, NP_001393418, NP_001393419, NP_001393420, NP_001393421, NP_001393422, NP_001393423, NP_001393424 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000333	TGFB_receptor	Family
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR003605	GS_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR045860	Snake_toxin-like_sf	Homologous_superfamily

Pfam: PF07714, PF08515

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)
• EC 2.7.11.30 — receptor protein serine/threonine kinase (BRENDA: 8 organisms, 67 substrates, 81 inhibitors, 4 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
ATP	0.0057–0.0088	2
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
KKVLTQMGSPSIRCS(P)SVS	0.26	1
KVLTQMGSPSVRCS(P)SMS	0.331	1
EEEEY	—	0

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[receptor-protein] + ATP = O-phospho-L-seryl-[receptor-protein] + ADP + H(+) (RHEA:18673)
• L-threonyl-[receptor-protein] + ATP = O-phospho-L-threonyl-[receptor-protein] + ADP + H(+) (RHEA:44880)

UniProt features (158 total): sequence variant 102, strand 17, helix 14, disulfide bond 5, modified residue 3, turn 3, binding site 2, topological domain 2, domain 2, signal peptide 1, chain 1, mutagenesis site 1, sequence conflict 1, glycosylation site 1, transmembrane region 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6SF3	X-RAY DIFFRACTION	2.3
3MY0	X-RAY DIFFRACTION	2.65
6SF1	X-RAY DIFFRACTION	2.8
6SF2	X-RAY DIFFRACTION	3.3
4FAO	X-RAY DIFFRACTION	3.36
7PPC	X-RAY DIFFRACTION	3.6
2LCR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P37023-F1	82.77	0.57

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 (1): 330 (proton acceptor)

Ligand- & substrate-binding residues (2): 229; 208–216

Post-translational modifications (3): 155, 160, 161

Disulfide bonds (5): 34–51, 36–41, 46–69, 77–89, 90–95

Glycosylation sites (1): 98

Mutagenesis-validated functional residues (1):

Position	Phenotype
74–76	affinity for bmp9 decreased by 200-fold.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-162582	Signal Transduction
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 475 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_571, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION

GO Biological Process (60): angiogenesis (GO:0001525), in utero embryonic development (GO:0001701), regulation of endothelial cell proliferation (GO:0001936), negative regulation of endothelial cell proliferation (GO:0001937), positive regulation of endothelial cell proliferation (GO:0001938), lymphangiogenesis (GO:0001946), blood vessel maturation (GO:0001955), blood vessel remodeling (GO:0001974), blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:0002043), endocardial cushion morphogenesis (GO:0003203), regulation of DNA replication (GO:0006275), regulation of DNA-templated transcription (GO:0006355), negative regulation of cell adhesion (GO:0007162), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), heart development (GO:0007507), blood circulation (GO:0008015), regulation of blood pressure (GO:0008217), negative regulation of cell population proliferation (GO:0008285), dorsal/ventral pattern formation (GO:0009953), negative regulation of endothelial cell migration (GO:0010596), negative regulation of gene expression (GO:0010629), cell differentiation (GO:0030154), negative regulation of cell growth (GO:0030308), negative regulation of cell migration (GO:0030336), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), positive regulation of epithelial cell differentiation (GO:0030858), positive regulation of chondrocyte differentiation (GO:0032332), wound healing, spreading of epidermal cells (GO:0035313), dorsal aorta morphogenesis (GO:0035912), regulation of blood vessel endothelial cell migration (GO:0043535), negative regulation of blood vessel endothelial cell migration (GO:0043537), negative regulation of endothelial cell differentiation (GO:0045602), positive regulation of endothelial cell differentiation (GO:0045603), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of angiogenesis (GO:0045766), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of focal adhesion assembly (GO:0051895)

GO Molecular Function (19): protein serine/threonine kinase activity (GO:0004674), transmembrane receptor protein serine/threonine kinase activity (GO:0004675), transforming growth factor beta receptor activity (GO:0005024), transforming growth factor beta receptor activity, type I (GO:0005025), ATP binding (GO:0005524), activin receptor activity, type I (GO:0016361), protein kinase binding (GO:0019901), SMAD binding (GO:0046332), metal ion binding (GO:0046872), activin binding (GO:0048185), transforming growth factor beta binding (GO:0050431), BMP receptor activity (GO:0098821), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), cytokine binding (GO:0019955), signaling receptor activity (GO:0038023)

GO Cellular Component (5): plasma membrane (GO:0005886), cell surface (GO:0009986), BMP receptor complex (GO:0070724), membrane (GO:0016020), signaling receptor complex (GO:0043235)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endothelial cell proliferation	4
anatomical structure formation involved in morphogenesis	2
regulation of endothelial cell proliferation	2
negative regulation of cellular process	2
transmembrane receptor protein serine/threonine kinase activity	2
protein binding	2
cellular anatomical structure	2
blood vessel morphogenesis	1
chordate embryonic development	1
regulation of epithelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
anatomical structure morphogenesis	1
lymph vessel morphogenesis	1
blood vessel development	1
anatomical structure maturation	1
tissue remodeling	1
sprouting angiogenesis	1
heart morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
DNA replication	1
regulation of DNA metabolic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell adhesion	1
regulation of cell adhesion	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
animal organ development	1
circulatory system development	1
circulatory system process	1
blood circulation	1
regulation of biological quality	1

Protein interactions and networks

STRING

2160 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACVRL1	GDF2	Q9UK05	999
ACVRL1	ENG	P17813	997
ACVRL1	BMP10	O95393	994
ACVRL1	ACVR2A	P27037	959
ACVRL1	BMPR2	Q13873	938
ACVRL1	TGFBR2	P37173	916
ACVRL1	OR2AG1	Q9H205	909
ACVRL1	SMAD9	O15198	897
ACVRL1	TGFB1	P01137	884
ACVRL1	SMAD4	Q13485	884
ACVRL1	SMAD5	Q99717	859
ACVRL1	ACVR1	Q04771	847
ACVRL1	BMP4	P12644	834
ACVRL1	ACVR2B	Q13705	736
ACVRL1	BMPR1B	P78366	731

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ACVRL1	PDXDC2P	psi-mi:“MI:0915”(physical association)	0.560
ACVR1	BMPR1A	psi-mi:“MI:0914”(association)	0.530
LRG1	ACVRL1	psi-mi:“MI:0915”(physical association)	0.500
ACVRL1	LRG1	psi-mi:“MI:0914”(association)	0.500
GDF2	ACVRL1	psi-mi:“MI:0915”(physical association)	0.500
ITGA5	ACVRL1	psi-mi:“MI:0915”(physical association)	0.400
ACVRL1	ENG	psi-mi:“MI:0914”(association)	0.350
ACVRL1	SLC25A24	psi-mi:“MI:0914”(association)	0.350

BioGRID (63): ACVRL1 (Affinity Capture-MS), ACVRL1 (Synthetic Lethality), PDXDC2P (Affinity Capture-MS), SLC25A24 (Affinity Capture-MS), ACVRL1 (Affinity Capture-MS), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), AMHR2 (Negative Genetic), CDK12 (Negative Genetic), CIT (Negative Genetic), LTC4S (Negative Genetic), TGFB1 (Affinity Capture-Western), ACVRL1 (Affinity Capture-MS), PDXDC2P (Affinity Capture-MS), ACVRL1 (Affinity Capture-Western)

ESM2 similar proteins: O00238, O08680, O42127, O42422, O46680, O73875, P09759, P22182, P29318, P29319, P29320, P29323, P36894, P36895, P36896, P36897, P36898, P37023, P37172, P54755, P54756, P54757, P54758, P54759, P54762, P70539, P80201, P80202, P80203, P80204, Q04771, Q05438, Q09488, Q15375, Q28041, Q5CD18, Q5RAN0, Q60629, Q61271, Q61288

Diamond homologs: A0A0P0XII1, A0A0R0HPY5, A7J1T2, C0LGD6, C0LGD8, C0LGD9, C0LGG3, C0LGR6, C0LGV0, O00238, O00506, O04086, O35607, O46680, O64556, O65440, P04627, P09560, P0C5E2, P10398, P10533, P14056, P15056, P18161, P20792, P27037, P27038, P27039, P27040, P27041, P27966, P28028, P34908, P36894, P36895, P36896, P36897, P36898, P37023, P37172

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
BMP10	up-regulates	ACVRL1	binding
GDF2	up-regulates	ACVRL1	binding
SMAD7	down-regulates	ACVRL1

Disease & clinical

Clinical variants and AI predictions

ClinVar

1250 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	371
Likely pathogenic	130
Uncertain significance	270
Likely benign	227
Benign	76

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1015010	NM_000020.3(ACVRL1):c.1411T>G (p.Cys471Gly)	Pathogenic
1066979	NM_000020.3(ACVRL1):c.106T>C (p.Cys36Arg)	Pathogenic
1066980	NM_000020.3(ACVRL1):c.1325T>C (p.Val442Ala)	Pathogenic
1069624	NM_000020.3(ACVRL1):c.362_374del (p.Leu121fs)	Pathogenic
1070651	NM_000020.3(ACVRL1):c.121T>G (p.Cys41Gly)	Pathogenic
1070764	NM_000020.3(ACVRL1):c.1297C>T (p.Pro433Ser)	Pathogenic
1072475	NM_000020.3(ACVRL1):c.78_81del (p.Ser27fs)	Pathogenic
1072776	NM_000020.3(ACVRL1):c.115_116del (p.Pro39fs)	Pathogenic
1073041	NM_000020.3(ACVRL1):c.329C>A (p.Ser110Ter)	Pathogenic
1073109	NC_000012.11:g.52308281_52308282insAlu	Pathogenic
1073797	NM_000020.3(ACVRL1):c.412_413del (p.Leu138fs)	Pathogenic
1074142	NM_000020.3(ACVRL1):c.131_132insCACA (p.Cys46fs)	Pathogenic
1074702	NM_000020.3(ACVRL1):c.1010del (p.Leu337fs)	Pathogenic
1074703	NM_000020.3(ACVRL1):c.1069C>T (p.Gln357Ter)	Pathogenic
1075285	NM_000020.3(ACVRL1):c.871A>T (p.Arg291Ter)	Pathogenic
1076534	NM_000020.3(ACVRL1):c.525+1G>T	Pathogenic
1163056	NM_000020.3(ACVRL1):c.525+2T>C	Pathogenic
1163532	NM_000020.3(ACVRL1):c.1073del (p.Gly358fs)	Pathogenic
1319603	NM_000020.3(ACVRL1):c.983A>C (p.His328Pro)	Pathogenic
1322795	NM_000020.3(ACVRL1):c.510del (p.Asp171fs)	Pathogenic
1322799	NM_000020.3(ACVRL1):c.505C>T (p.Gln169Ter)	Pathogenic
1330267	NM_000020.3(ACVRL1):c.68del (p.Pro23fs)	Pathogenic
1330268	NM_000020.3(ACVRL1):c.205T>C (p.Cys69Arg)	Pathogenic
1330270	NM_000020.3(ACVRL1):c.868C>T (p.Gln290Ter)	Pathogenic
1330572	NM_000020.3(ACVRL1):c.961C>T (p.Gln321Ter)	Pathogenic
1359265	NM_000020.3(ACVRL1):c.130_143del (p.Pro44fs)	Pathogenic
1363480	NM_000020.3(ACVRL1):c.375del (p.Val126fs)	Pathogenic
1372770	NM_000020.3(ACVRL1):c.1347del (p.Thr450fs)	Pathogenic
1382311	NM_000020.3(ACVRL1):c.142G>A (p.Gly48Arg)	Pathogenic
1387054	NM_000020.3(ACVRL1):c.1419C>G (p.Tyr473Ter)	Pathogenic

SpliceAI

1650 predictions. Top by Δscore:

Variant	Effect	Δscore
12:51907693:GAG:G	donor_gain	1.0000
12:51907696:GTG:G	donor_loss	1.0000
12:51912464:CTGCA:C	acceptor_loss	1.0000
12:51912465:TGCA:T	acceptor_loss	1.0000
12:51912466:GCA:G	acceptor_loss	1.0000
12:51912467:CAGGG:C	acceptor_loss	1.0000
12:51912468:AG:A	acceptor_gain	1.0000
12:51912468:AGG:A	acceptor_gain	1.0000
12:51912468:AGGGA:A	acceptor_loss	1.0000
12:51912469:G:A	acceptor_loss	1.0000
12:51912469:GG:G	acceptor_gain	1.0000
12:51912469:GGG:G	acceptor_gain	1.0000
12:51912532:CAGGG:C	donor_loss	1.0000
12:51912534:GG:G	donor_gain	1.0000
12:51912534:GGGT:G	donor_loss	1.0000
12:51912535:GG:G	donor_gain	1.0000
12:51912536:G:GG	donor_gain	1.0000
12:51912537:T:G	donor_loss	1.0000
12:51913349:GG:G	donor_gain	1.0000
12:51913350:GG:G	donor_gain	1.0000
12:51913717:G:GT	donor_gain	1.0000
12:51913719:A:T	donor_gain	1.0000
12:51913745:C:G	donor_gain	1.0000
12:51913753:G:GT	donor_gain	1.0000
12:51914592:G:T	donor_gain	1.0000
12:51915220:CACA:C	acceptor_loss	1.0000
12:51915223:A:AG	acceptor_gain	1.0000
12:51915224:G:A	acceptor_loss	1.0000
12:51915224:G:GG	acceptor_gain	1.0000
12:51915465:TC:T	donor_gain	1.0000

AlphaMissense

3264 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:51914444:G:C	G211R	1.000
12:51914444:G:T	G211C	1.000
12:51914454:G:A	G214D	1.000
12:51914454:G:T	G214V	1.000
12:51914493:C:A	A227D	1.000
12:51914496:T:A	V228D	1.000
12:51914498:A:C	K229Q	1.000
12:51914498:A:G	K229E	1.000
12:51914500:G:C	K229N	1.000
12:51914500:G:T	K229N	1.000
12:51914504:T:C	F231L	1.000
12:51914505:T:C	F231S	1.000
12:51914506:C:A	F231L	1.000
12:51914506:C:G	F231L	1.000
12:51914528:T:A	W239R	1.000
12:51914528:T:C	W239R	1.000
12:51914530:G:C	W239C	1.000
12:51914530:G:T	W239C	1.000
12:51914535:G:C	R241P	1.000
12:51914538:A:T	E242V	1.000
12:51914539:G:C	E242D	1.000
12:51914539:G:T	E242D	1.000
12:51915227:T:C	F259L	1.000
12:51915229:C:A	F259L	1.000
12:51915229:C:G	F259L	1.000
12:51915240:A:T	D263V	1.000
12:51915270:T:C	L273P	1.000
12:51915276:T:A	L275H	1.000
12:51915276:T:C	L275P	1.000
12:51915390:T:C	L313P	1.000

dbSNP variants (sampled 300 via entrez): RS1000036817 (12:51910336 A>G), RS1000255663 (12:51923235 G>A), RS1000299910 (12:51915593 C>G), RS1000420952 (12:51908879 G>C), RS1000501488 (12:51921984 A>G,T), RS1000575927 (12:51915143 C>G,T), RS1000645855 (12:51916506 T>A,C), RS1000654467 (12:51917172 C>T), RS1000788644 (12:51910462 A>G), RS1002048974 (12:51921298 G>T), RS1002119822 (12:51905996 G>A,C), RS1002131208 (12:51916755 C>T), RS1002184603 (12:51907469 G>A,C), RS1002619607 (12:51905697 G>A), RS1002651703 (12:51920078 C>A,T)

Disease associations

OMIM: gene MIM:601284 | disease phenotypes: MIM:600376, MIM:134500, MIM:306700, MIM:187300, MIM:178600

GenCC curated gene-disease

Disease	Classification	Inheritance
telangiectasia, hereditary hemorrhagic, type 2	Definitive	Autosomal dominant
hereditary hemorrhagic telangiectasia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
telangiectasia, hereditary hemorrhagic, type 2	Definitive	AD

Mondo (8): telangiectasia, hereditary hemorrhagic, type 2 (MONDO:0010880), hemophilia A (MONDO:0010602), thrombocytopenia (MONDO:0002049), pulmonary arterial hypertension (MONDO:0015924), hereditary hemorrhagic telangiectasia (MONDO:0019180), pulmonary hypertension, primary, 1 (MONDO:0024533), heritable pulmonary arterial hypertension (MONDO:0017148), telangiectasis (MONDO:0001576)

Orphanet (5): Hereditary hemorrhagic telangiectasia (Orphanet:774), Hemophilia A (Orphanet:98878), Pulmonary arterial hypertension (Orphanet:182090), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Heritable pulmonary arterial hypertension (Orphanet:275777)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000214	Lip telangiectasia
HP:0000227	Tongue telangiectasia
HP:0000228	Oral cavity telangiectasia
HP:0000421	Epistaxis
HP:0000434	Nasal mucosa telangiectasia
HP:0000471	Gastrointestinal angiodysplasia
HP:0000524	Conjunctival telangiectasia
HP:0000822	Hypertension
HP:0000961	Cyanosis
HP:0001009	Telangiectasia
HP:0001217	Clubbing
HP:0001232	Nail bed telangiectasia
HP:0001250	Seizure
HP:0001342	Cerebral hemorrhage
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001635	Congestive heart failure
HP:0001694	Right-to-left shunt
HP:0001901	Polycythemia
HP:0001903	Anemia
HP:0002040	Esophageal varix
HP:0002076	Migraine
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002105	Hemoptysis
HP:0002138	Subarachnoid hemorrhage
HP:0002140	Ischemic stroke
HP:0002204	Pulmonary embolism

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001791_24	Urate levels	2.000000e-09
GCST004607_46	Plateletcrit	4.000000e-11
GCST004610_130	White blood cell count	2.000000e-14
GCST004625_121	Monocyte count	1.000000e-09
GCST004626_117	Myeloid white cell count	5.000000e-13
GCST005994_12	Hematocrit	9.000000e-10
GCST005995_3	Hemoglobin	9.000000e-12
GCST007931_63	Medication use (HMG CoA reductase inhibitors)	9.000000e-09
GCST010083_307	Hemoglobin levels	7.000000e-10
GCST90000025_967	Appendicular lean mass	2.000000e-10
GCST90002384_309	Hemoglobin	6.000000e-10
GCST90002388_433	Lymphocyte count	8.000000e-09
GCST90002393_413	Monocyte count	4.000000e-13
GCST90002398_142	Neutrophil count	2.000000e-15
GCST90002400_88	Plateletcrit	3.000000e-21
GCST90002402_379	Platelet count	2.000000e-10
GCST90002407_285	White blood cell count	1.000000e-20

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0007985	platelet crit
EFO:0005091	monocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count
EFO:0004833	neutrophil count
EFO:0004309	platelet count

MeSH disease descriptors (5)

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
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D013683	Telangiectasia, Hereditary Hemorrhagic	C14.907.454.900; C14.907.823.780; C15.378.463.515.900; C16.131.240.850.968
D013684	Telangiectasis	C14.907.823
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5311 (SINGLE PROTEIN), CHEMBL6066857 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 90,964 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL5416410	DASATINIB	4	655
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL495727	AT-9283	2	1,376
CHEMBL5314579	ZILURGISERTIB	2	26
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL5095192	PF-06952229	1	289

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type I receptor serine/threonine kinases

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
compound 13d [PMID: 23639540]	Inhibition	8.3	pIC50
compound 13r [PMID: 23639540]	Inhibition	8.3	pIC50
LDN-214117	Inhibition	7.57	pIC50
compound 13a [PMID: 23639540]	Inhibition	7.38	pIC50
ML347	Inhibition	7.34	pIC50
panulisib	Inhibition	7.33	pIC50
zilurgisertib	Inhibition	6.49	pIC50

Binding affinities (BindingDB)

127 measured of 158 human assays (158 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[4-amino-5-[4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]butan-1-ol	IC50	1 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
4-[4-amino-5-[3-fluoro-4-(hydroxymethyl)-5-methoxyphenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexan-1-ol	IC50	1 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	1.18 nM	US-8822500: Tyrosine kinase inhibitors
[4-amino-5-[4-(hydroxymethyl)-3-methoxyphenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-cyclopropylmethanol	IC50	1.2 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-amino-5-[3,5-difluoro-4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-cyclopropylmethanol	IC50	1.3 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-[4-amino-7-[(3R)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl]methanol	IC50	1.9 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-difluorophenyl]methanol	IC50	1.9 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-propylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]methanol	IC50	2 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
4-[4-amino-5-[3,5-difluoro-4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexan-1-ol	IC50	2 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-[4-amino-7-(2-amino-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl]methanol	IC50	2 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluoro-6-methoxyphenyl]methanol	IC50	2 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
6-[2-(dimethylamino)ethyl]-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3,5-dihydropyrrolo[3,4-f]benzimidazol-7-one	IC50	2.06 nM	US-8822500: Tyrosine kinase inhibitors
[4-[4-amino-7-(2-ethyl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl]methanol	IC50	2.6 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-propylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-difluorophenyl]methanol	IC50	2.8 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
6-(1-methylpiperidin-4-yl)-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3,5-dihydropyrrolo[3,4-f]benzimidazol-7-one	IC50	3.48 nM	US-8822500: Tyrosine kinase inhibitors
1-[4-amino-5-[3,5-difluoro-4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanol	IC50	3.8 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
3-[4-amino-5-[4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]propan-1-ol	IC50	4 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-[4-amino-7-(2-methyl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl]methanol	IC50	4 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluoro-6-methylphenyl]methanol	IC50	4 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluoro-6-methylphenyl]methanol	IC50	4 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-ethyl-6-fluorophenyl]methanol	IC50	4 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-[4-amino-7-[2-(aminomethyl)-1,3-thiazol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl]methanol	IC50	4.1 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-[4-amino-7-(2-methyl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl]methanol	IC50	5.3 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
3-[4-amino-5-[3,5-difluoro-4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidin-3-ol	IC50	5.7 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-amino-5-[3-ethyl-5-fluoro-4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-cyclopropylmethanol	IC50	5.7 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-[4-amino-7-[(3S)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl]methanol	IC50	5.9 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
US8822500, [24A]	IC50	5.99 nM	US-8822500: Tyrosine kinase inhibitors
2-[4-[1-(2,5-difluorophenyl)propan-2-ylamino]-2-oxopiperidin-3-yl]-6-(1-methylpiperidin-4-yl)-3H-pyrrolo[3,4-f]benzimidazole-5,7-dione	IC50	6.35 nM	US-8822500: Tyrosine kinase inhibitors
4-[6-[4-[(2R,6S)-2,6-dimethylpiperazin-1-yl]phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-2-methylquinoline	IC50	7.7 nM	US-9682983: BMP inhibitors and methods of use thereof
[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]methanol	IC50	8 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
5-[6-[4-[(2S,6R)-2,6-dimethylpiperazin-1-yl]phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	8 nM	US-9682983: BMP inhibitors and methods of use thereof
4-[6-[4-[(2S,6R)-2,6-dimethylpiperazin-1-yl]phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	10 nM	US-9682983: BMP inhibitors and methods of use thereof
US8822500, [24]	IC50	10.4 nM	US-8822500: Tyrosine kinase inhibitors
4-[6-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	12 nM	US-9682983: BMP inhibitors and methods of use thereof
5-[6-[6-(2-piperazin-1-ylethoxy)-3-pyridinyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	14 nM	US-9682983: BMP inhibitors and methods of use thereof
6-[2-(dimethylamino)ethyl]-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3H-pyrrolo[3,4-f]benzimidazole-5,7-dione	IC50	14 nM	US-8822500: Tyrosine kinase inhibitors
4-[6-(3-fluoro-4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	15 nM	US-9682983: BMP inhibitors and methods of use thereof
1-[4-amino-5-[3,5-difluoro-4-(hydroxymethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]cyclohexan-1-ol	IC50	15 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
4-[6-(5-piperazin-1-yl-2-pyridinyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	16 nM	US-9682983: BMP inhibitors and methods of use thereof
5-[6-[3-chloro-4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	16 nM	US-9682983: BMP inhibitors and methods of use thereof
[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl]methanol	IC50	17 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
5-[6-[6-[2-(4-methylpiperazin-1-yl)ethoxy]-3-pyridinyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	17 nM	US-9682983: BMP inhibitors and methods of use thereof
US8822500, [17]	IC50	17.5 nM	US-8822500: Tyrosine kinase inhibitors
5-piperazin-1-yl-2-(3-quinolin-4-ylpyrazolo[1,5-a]pyrimidin-6-yl)-1,3-thiazole	IC50	19 nM	US-9682983: BMP inhibitors and methods of use thereof
[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl]methanol	IC50	19 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-difluorophenyl]methanol	IC50	21 nM	US-9040691: Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors
4-[6-[6-[(2S,6R)-2,6-dimethylpiperazin-1-yl]-3-pyridinyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	22 nM	US-9682983: BMP inhibitors and methods of use thereof
4-[6-[6-(2-piperazin-1-ylethoxy)-3-pyridinyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	22 nM	US-9682983: BMP inhibitors and methods of use thereof
2-methyl-4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	23 nM	US-9682983: BMP inhibitors and methods of use thereof
2-methyl-4-[6-(4-piperidin-4-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	IC50	23 nM	US-9682983: BMP inhibitors and methods of use thereof

ChEMBL bioactivities

578 potent at pChembl≥5 of 590 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3667966
9.00	IC50	1	nM	CHEMBL3667990
8.96	IC50	1.1	nM	CHEMBL3818173
8.92	IC50	1.2	nM	CHEMBL3667999
8.89	IC50	1.3	nM	CHEMBL3667967
8.87	IC50	1.361	nM	CHEMBL1980995
8.74	IC50	1.8	nM	CHEMBL1230714
8.72	IC50	1.9	nM	CHEMBL3667973
8.72	IC50	1.9	nM	CHEMBL3668000
8.70	IC50	2	nM	CHEMBL3667963
8.70	IC50	2	nM	CHEMBL3667969
8.70	IC50	2	nM	CHEMBL3667979
8.70	IC50	2	nM	CHEMBL3667991
8.59	IC50	2.6	nM	CHEMBL3667978
8.55	IC50	2.8	nM	CHEMBL3667964
8.54	Kd	2.9	nM	CHEMBL1241674
8.52	IC50	3	nM	CHEMBL3667973
8.49	IC50	3.2	nM	CHEMBL3667999
8.46	IC50	3.5	nM	CHEMBL3667999
8.42	IC50	3.8	nM	CHEMBL3668001
8.40	IC50	4	nM	CHEMBL3818173
8.40	IC50	4	nM	CHEMBL3667965
8.40	IC50	4	nM	CHEMBL3667975
8.40	IC50	4	nM	CHEMBL3667992
8.40	IC50	4	nM	CHEMBL3667993
8.40	IC50	4	nM	CHEMBL3667997
8.40	IC50	4	nM	CHEMBL5989551
8.40	IC50	4	nM	CHEMBL4280599
8.39	IC50	4.1	nM	CHEMBL3667995
8.36	IC50	4.4	nM	CHEMBL3667970
8.33	IC50	4.701	nM	CHEMBL3671311
8.28	IC50	5.3	nM	CHEMBL3667976
8.24	IC50	5.7	nM	CHEMBL3667971
8.24	IC50	5.7	nM	CHEMBL3667998
8.24	IC50	5.8	nM	CHEMBL4280599
8.23	IC50	5.9	nM	CHEMBL3667974
8.23	IC50	5.9	nM	CHEMBL5184000
8.17	IC50	6.7	nM	CHEMBL3667969
8.16	IC50	6.9	nM	CHEMBL3667970
8.15	IC50	7	nM	CHEMBL4548795
8.10	IC50	8	nM	CHEMBL3667972
8.04	IC50	9.157	nM	CHEMBL3671318
8.01	IC50	9.812	nM	CHEMBL3671309
8.00	IC50	10	nM	CHEMBL5199417
8.00	IC50	10	nM	CHEMBL5186341
7.96	IC50	11	nM	CHEMBL5205781
7.96	IC50	11	nM	CHEMBL5749457
7.95	IC50	11.13	nM	CHEMBL513147
7.92	IC50	12	nM	ENTRECTINIB
7.89	IC50	13	nM	CHEMBL5083143

PubChem BioAssay actives

113 with measured affinity, of 470 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
3-[6-amino-5-(3,4,5-trimethoxyphenyl)-3-pyridinyl]phenol	1877422: Inhibition of GST-tagged human recombinant ALK1 expressed in baculovirus expression system using casein as substrate in presence of [gamma-32P]ATP incubated for 45 mins by Microscint-20 scintillation counting analysis	ic50	0.0018	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624778: Binding constant for ACVRL1 kinase domain	kd	0.0029	uM
2-methyl-4-[7-(4-piperazin-2-ylphenyl)imidazo[1,2-a]pyridin-3-yl]quinoline	1722082: Inhibition of human ALK1 using casein as substrate by [gamma-33P]-ATP assay	ic50	0.0050	uM
4-[6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0050	uM
4-[4-(3-quinolin-4-ylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]morpholine	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0050	uM
methyl (3R,5S)-3,5-dimethyl-4-[3-[6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate	1870521: Inhibition of recombinant human C-terminal GST tagged ALK1 (144 to end residues) expressed in baculovirus assessed as loss of peptide phosphorylation activity using peptide substrate in presence of ATP and measured after 1 hrs by HTRF assay	ic50	0.0059	uM
2-fluoro-6-methoxy-4-[4-methyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]-3-pyridinyl]benzamide	2113164: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]ATP and 10 uM ATP by radiometric assay	ic50	0.0070	uM
[(3S,5R)-3,5-dimethyl-4-[3-[6-[(3R)-3-methylpiperazin-1-yl]-3-pyridinyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazin-1-yl]-pyrrolidin-1-ylmethanone	1870521: Inhibition of recombinant human C-terminal GST tagged ALK1 (144 to end residues) expressed in baculovirus assessed as loss of peptide phosphorylation activity using peptide substrate in presence of ATP and measured after 1 hrs by HTRF assay	ic50	0.0100	uM
methyl (3S,5R)-3,5-dimethyl-4-[3-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate	1870521: Inhibition of recombinant human C-terminal GST tagged ALK1 (144 to end residues) expressed in baculovirus assessed as loss of peptide phosphorylation activity using peptide substrate in presence of ATP and measured after 1 hrs by HTRF assay	ic50	0.0100	uM
8-amino-2-cyclohexyl-5-(1-piperidin-3-ylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0110	uM
4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	1431776: Inhibition of human ALK1 using casein as substrate in presence of 10 uM ATP by radiometric kinase assay	ic50	0.0111	uM
6-(4-piperazin-1-ylphenyl)-3-quinolin-4-ylfuro[3,2-b]pyridine	2113164: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]ATP and 10 uM ATP by radiometric assay	ic50	0.0130	uM
5-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0144	uM
1-[4-[4-methyl-5-(3,4,5-trimethoxyphenyl)-3-pyridinyl]phenyl]piperazine	1665327: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]-ATP by radiometric hotspot assay	ic50	0.0150	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1424903: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0150	uM
8-amino-2-cyclohexyl-5-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0150	uM
5-(4-acetyl-1H-pyrrol-2-yl)-2-[cyclopropyl-[1-(3-methoxy-4-pyridinyl)pyrazol-4-yl]amino]-1,3-thiazole-4-carboxamide	2112251: Inhibition of ALK1 (unknown origin) by TR-FRET assay	ic50	0.0166	uM
8-amino-2-cyclohexyl-5-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0170	uM
methyl (3S,5R)-3,5-dimethyl-4-[3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate	1870521: Inhibition of recombinant human C-terminal GST tagged ALK1 (144 to end residues) expressed in baculovirus assessed as loss of peptide phosphorylation activity using peptide substrate in presence of ATP and measured after 1 hrs by HTRF assay	ic50	0.0190	uM
methyl (3S,5R)-4-[3-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3,5-dimethylpiperazine-1-carboxylate	1870521: Inhibition of recombinant human C-terminal GST tagged ALK1 (144 to end residues) expressed in baculovirus assessed as loss of peptide phosphorylation activity using peptide substrate in presence of ATP and measured after 1 hrs by HTRF assay	ic50	0.0220	uM
8-amino-2-cyclohexyl-5-[1-(piperidin-4-ylmethyl)pyrazol-4-yl]-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0250	uM
[4-[6-[4-(4-methylpiperazin-1-yl)phenyl]furo[3,2-b]pyridin-3-yl]phenyl]methanol	2113164: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]ATP and 10 uM ATP by radiometric assay	ic50	0.0250	uM
4-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0265	uM
2-(2-adamantyl)-8-amino-5-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0270	uM
4-[6-(4-propan-2-yloxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0270	uM
1-[4-[6-methyl-5-(3,4,5-trimethoxyphenyl)-3-pyridinyl]phenyl]piperazine	1186986: Inhibition of ALK1 (unknown origin) expressed in HEK293T cells after 30 mins by luciferase reporter gene assay	ic50	0.0270	uM
8-amino-2-cyclobutyl-5-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0290	uM
5-[1-(1-acetylpiperidin-4-yl)pyrazol-4-yl]-8-amino-2-cyclohexyl-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0310	uM
6-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)furo[3,2-b]pyridine	2113164: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]ATP and 10 uM ATP by radiometric assay	ic50	0.0360	uM
8-amino-2-cyclohexyl-5-[1-(oxetan-3-yl)pyrazol-4-yl]-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0390	uM
2-methyl-4-[7-(4-piperazin-1-ylphenyl)imidazo[1,2-a]pyridin-3-yl]quinoline	1722082: Inhibition of human ALK1 using casein as substrate by [gamma-33P]-ATP assay	ic50	0.0391	uM
2,5-dimethyl-6-quinolin-4-yl-3H-quinazolin-4-one	1399002: Binding affinity to human ALK1 by KdELECT assay	kd	0.0410	uM
3-(2-methylquinolin-4-yl)-6-(4-piperazin-1-ylphenyl)furo[3,2-b]pyridine	2113164: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]ATP and 10 uM ATP by radiometric assay	ic50	0.0410	uM
8-amino-2-cyclohexyl-5-[1-(piperidin-3-ylmethyl)pyrazol-4-yl]-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0420	uM
4-[4-[3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0421	uM
2-amino-5-[3-fluoro-4-[[(2R)-2-methylpyrrolidin-1-yl]methyl]phenyl]-N-(4-hydroxy-4-methylcyclohexyl)pyridine-3-carboxamide	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0450	uM
8-amino-2-cyclohexyl-5-(1-propan-2-ylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0450	uM
5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0460	uM
8-amino-2-cyclohexyl-5-(1-cyclopentylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0480	uM
4-[6-[4-(1-pyrrolidin-1-ylethyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]naphthalene-1-sulfonamide	1417559: Inhibition of ALK1 (unknown origin) using Ulight topo IIa (Thr 1342) peptide as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by TR-FRET analysis	ic50	0.0510	uM
6-(4-methoxyphenyl)-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0524	uM
6-(4-piperazin-1-ylphenyl)-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	750132: Inhibition of ALK1 (unknown origin)	ic50	0.0550	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624778: Binding constant for ACVRL1 kinase domain	kd	0.0570	uM
8-amino-2-(4-hydroxy-4-methylcyclohexyl)-5-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2,7-naphthyridin-1-one	1877425: Inhibition of ALK1 (unknown origin)	ic50	0.0610	uM
(4S,9S,10S)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),15,17-triene-2,8-dione	1431757: Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]-ATP by scintillation counting method	ic50	0.0620	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624778: Binding constant for ACVRL1 kinase domain	kd	0.0690	uM
5-(4-acetyl-1H-pyrrol-2-yl)-2-[cyclopropyl-[1-(3-fluoro-4-pyridinyl)pyrazol-4-yl]amino]-1,3-thiazole-4-carboxamide	2112251: Inhibition of ALK1 (unknown origin) by TR-FRET assay	ic50	0.0737	uM
6,8-difluoro-2-methyl-4-[7-(4-piperazin-2-ylphenyl)imidazo[1,2-a]pyridin-3-yl]quinoline	1722082: Inhibition of human ALK1 using casein as substrate by [gamma-33P]-ATP assay	ic50	0.0892	uM
6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	750132: Inhibition of ALK1 (unknown origin)	ic50	0.1063	uM
3-amino-6-[2-chloro-4-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl]-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)pyrazine-2-carboxamide	1866687: Inhibition of wild type ALK1 (unknown origin) assessed as enzymatic activity by microfluidic mobility shift assay	ic50	0.1200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment	2
Dexamethasone	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression, decreases reaction, increases cleavage, increases expression, increases phosphorylation	2
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
kojic acid	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
2,2-(2-chlorophenyl-4’-chlorophenyl)-1,1-dichloroethene	affects cotreatment, increases expression	1
tamibarotene	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
Arsenic Trioxide	decreases expression	1
Aldrin	affects cotreatment, increases expression	1
Arbutin	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Dichlorodiphenyldichloroethane	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	affects cotreatment, increases expression	1
Dieldrin	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Naled	affects expression	1
Oxygen	affects reaction, decreases expression	1

ChEMBL screening assays

213 unique, capped per target: 207 binding, 3 functional, 2 toxicity, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032242	Binding	Inhibition of ACVRL1 at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem
CHEMBL4626188	ADMET	Inhibition of human ALK1 using casein as substrate in presence of [gamma-33P]-ATP by radiometric hotspot assay	Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma. — J Med Chem
CHEMBL5133118	Toxicity	Inhibition of GST-tagged human recombinant ALK1 expressed in baculovirus expression system using casein as substrate in presence of [gamma-32P]ATP incubated for 45 mins by Microscint-20 scintillation counting analysis	Inhibition of ALK2 with bicyclic pyridyllactams. — Bioorg Med Chem Lett

Cellosaurus cell lines

15 cell lines: 11 induced pluripotent stem cell, 3 cancer cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0W8	KMUGMCi001-A	Induced pluripotent stem cell	Female
CVCL_D2HV	Abcam Raji ACVRL1 KO	Cancer cell line	Male
CVCL_F1J4	LUMCi017-A-1	Induced pluripotent stem cell	Male
CVCL_F1J5	LUMCi017-A-2	Induced pluripotent stem cell	Male
CVCL_F1J6	LUMCi018-A-1	Induced pluripotent stem cell	Male
CVCL_F1J7	LUMCi018-A-2	Induced pluripotent stem cell	Male
CVCL_UQ06	Abcam Jurkat ACVRL1 KO	Cancer cell line	Male
CVCL_W908	TRP3	Telomerase immortalized cell line	Female
CVCL_WQ90	Abcam K-562 ACVRL1 KO	Cancer cell line	Female
CVCL_ZA21	LUMCi017-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02389959	PHASE4	COMPLETED	Intranasal Bevacizumab for HHT-Related Epistaxis
NCT00002386	PHASE4	COMPLETED	Effect of Indinavir Plus Two Other Anti-HIV Drugs on Blood Clotting in HIV-Positive Males With Hemophilia
NCT00092976	PHASE4	COMPLETED	Study Evaluating ReFacto® in Hemophilia A Undergoing Major Surgery
NCT00151385	PHASE4	WITHDRAWN	Study Evaluating Inhibitor Specificity in Hemophilia A
NCT00168051	PHASE4	WITHDRAWN	Study Comparing Blood Levels of ReFacto and Advante in Hemophilia A
NCT00243386	PHASE4	COMPLETED	Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
NCT00284193	PHASE4	COMPLETED	Combination Therapy of Low Doses of rFVIIa and FEIBA for Severe Hemophilia A Patients With an Inhibitor to Factor VIII
NCT00289536	PHASE4	COMPLETED	Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
NCT00357656	PHASE4	COMPLETED	Phase 3/4 Study of a Recombinant Protein-Free Factor VIII (rAHF-PFM): Comparison of Continuous Infusion Versus Intermittent Bolus Infusion in Hemophilia A Subjects Undergoing Major Orthopedic Surgery
NCT00586521	PHASE4	COMPLETED	BAY14-2222 Prophylaxis and Joint Function Improvement (Adults)
NCT00621673	PHASE4	TERMINATED	Assessment of the Risk of Inhibitor Formation in Previously Treated Patients With Severe Hemophilia A
NCT00632814	PHASE4	COMPLETED	Russian Kogenate Pediatric Study
NCT00638001	PHASE4	COMPLETED	Impact of Conservative Treatment by Custom-made Orthoses in Patients With Haemophilic Ankle Arthropathy
NCT00666406	PHASE4	COMPLETED	Pharmacokinetic Comparison of Advate rAHF-PFM With Recombinate rAHF in Patients With Severe Hemophilia A
NCT00765726	PHASE4	TERMINATED	Study Evaluating The Safety Of Xyntha In Usual Care Settings
NCT00884390	PHASE4	TERMINATED	Study Evaluating Safety Of Patients Switching To ReFacto AF In Usual Care Settings
NCT00914459	PHASE4	COMPLETED	Study Evaluating Safety And Efficacy Of Moroctocog Alfa (AF-CC) In Previously Treated Hemophilia A Patients
NCT00916032	PHASE4	COMPLETED	Pharmacokinetic Study of ADVATE 3000 IU in Previously Treated Patients With Severe Hemophilia A
NCT00927667	PHASE4	COMPLETED	Joint Status in Subjects With Severe Hemophilia A in Relation to Different Treatment Regimens
NCT00950170	PHASE4	COMPLETED	Study of Safety And Efficacy Of ReFacto AF In Previously Untreated Hemophilia A Patients In The Usual Care Setting
NCT01064284	PHASE4	COMPLETED	Survey of Inhibitors in Plasma-Product Exposed Toddlers
NCT01748201	PHASE4	COMPLETED	Viscosupplementation in Patients With Hemophilic Arthropathy
NCT01810666	PHASE4	COMPLETED	Prophylaxis Versus on Demand Treatment for Children With Hemophilia A
NCT01811875	PHASE4	TERMINATED	Post-Marketing Safety Study Following Long-Term Prophylactic OptivateTreatment in Subjects With Severe Haemophilia A
NCT02170402	PHASE4	COMPLETED	China ADVATE PTP Study
NCT02314325	PHASE4	UNKNOWN	Subclinical Joint Bleeding in Irish Adults With Severe Haemophilia A on Personalised Prophylaxis Regimens
NCT02479087	PHASE4	UNKNOWN	Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients
NCT02492984	PHASE4	COMPLETED	PF-05208756, Moroctocog Alfa (AF-CC), Xyntha For Hemophilia A
NCT02697370	PHASE4	COMPLETED	Efficacy and Cost Effectiveness of Pharmacokinetic Dosing in Haemophilia A
NCT02727647	PHASE4	COMPLETED	Comparison of Different Prophylaxis Regimens for Moderate to Severe Hemophilia A Pediatric Patients
NCT03103542	PHASE4	COMPLETED	Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies
NCT03204539	PHASE4	TERMINATED	INdividualized ITI Based on Fviii(ATE) Protection by VWF
NCT03361137	PHASE4	TERMINATED	Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures
NCT03379974	PHASE4	COMPLETED	Exercise Versus DDAVP in Patients With Mild Hemophilia A
NCT03449342	PHASE4	COMPLETED	Research Study to Look at Side Effects During Regular Injection With Factor VIII Medicine Named Turoctocog Alfa for a 8 Weeks Period
NCT03915080	PHASE4	COMPLETED	Optimizing the Use of Prophylaxis in Patients With Severe Haemophilia A
NCT03947567	PHASE4	UNKNOWN	Safety and Efficacy of Long-term Treatment With SCT800 in Previously Treated Hemophilia A Patients.
NCT04085458	PHASE4	COMPLETED	Study to Gain More Information on How Safe and Effective Jivi Works in Patients With Severe Hemophilia A (Post-marketing Investigation)
NCT04396639	PHASE4	COMPLETED	Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Hemophilia A Patients
NCT04565236	PHASE4	COMPLETED	A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A