Target Information
| Target General Information | Top | |||||
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| Target ID |
T36959
(Former ID: TTDC00338)
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| Target Name |
Activin receptor-like kinase-1 (ACVRL1)
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| Synonyms |
Serine/threonine-protein kinase receptor R3; SKR3; Activin receptor-like kinase 1; ALK-1; ACVRLK1; ACVRL1
Click to Show/Hide
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| Gene Name |
ACVRL1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 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 bindactivin as well.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.30
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| Sequence |
MTLGSPRKGLLMLLMALVTQGDPVKPSRGPLVTCTCESPHCKGPTCRGAWCTVVLVREEG
RHPQEHRGCGNLHRELCRGRPTEFVNHYCCDSHLCNHNVSLVLEATQPPSEQPGTDGQLA LILGPVLALLALVALGVLGLWHVRRRQEKQRGLHSELGESSLILKASEQGDSMLGDLLDS DCTTGSGSGLPFLVQRTVARQVALVECVGKGRYGEVWRGLWHGESVAVKIFSSRDEQSWF RETEIYNTVLLRHDNILGFIASDMTSRNSSTQLWLITHYHEHGSLYDFLQRQTLEPHLAL RLAVSAACGLAHLHVEIFGTQGKPAIAHRDFKSRNVLVKSNLQCCIADLGLAVMHSQGSD YLDIGNNPRVGTKRYMAPEVLDEQIRTDCFESYKWTDIWAFGLVLWEIARRTIVNGIVED YRPPFYDVVPNDPSFEDMKKVVCVDQQTPTIPNRLAADPVLSGLAQMMRECWYPNPSARL TALRIKKTLQKISNSPEKPKVIQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | PF-03446962 | Drug Info | Phase 2 | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | PF-03446962 | Drug Info | [1] | |||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | LDN-214117 | Drug Info | [3] | |||
| 2 | ML347 | Drug Info | [4] | |||
| 3 | PMID23639540C13a | Drug Info | [4] | |||
| 4 | PMID23639540C13d | Drug Info | [4] | |||
| 5 | PMID23639540C13r | Drug Info | [4] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 4-(6-(4-(Piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline | Ligand Info | |||||
| Structure Description | Crystal structure of the ACVRL1 (ALK1) kinase domain bound to LDN-193189 | PDB:3MY0 | ||||
| Method | X-ray diffraction | Resolution | 2.65 Å | Mutation | No | [5] |
| PDB Sequence |
MQRTVARQVA
203 LVECVGKGRY213 GEVWRGLWHG223 ESVAVKIFSS233 RDEQSWFRET243 EIYNTVLLRH 253 DNILGFIASD263 MTSTQLWLIT277 HYHEHGSLYD287 FLQRQTLEPH297 LALRLAVSAA 307 CGLAHLHVEI317 FGTQGKPAIA327 HRDFKSRNVL337 VKSNLQCCIA347 DLGLAVMHSQ 357 GSDYLDIGNN367 PRVGTKRYMA377 PEVLDEQIRT387 DCFESYKWTD397 IWAFGLVLWE 407 IARRTIVNGI417 VEDYRPPFYD427 VVPNDPSFED437 MKKVVCVDQQ447 TPTIPNRLAA 457 DPVLSGLAQM467 MRECWYPNPS477 ARLTALRIKK487 TLQKIS
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VAL208
3.702
VAL216
3.556
ALA227
3.269
LYS229
3.378
GLU242
4.920
LEU257
4.007
LEU275
3.953
THR277
3.700
HIS278
3.661
TYR279
3.500
HIS280
3.724
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cytokine-cytokine receptor interaction | hsa04060 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 14 | Degree centrality | 1.50E-03 | Betweenness centrality | 1.33E-04 |
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| Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 3.63E-01 |
| Neighborhood connectivity | 2.18E+01 | Topological coefficient | 1.53E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | TGF-beta signaling pathway | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | ALK1 pathway | |||||
| 2 | ALK1 signaling events | |||||
| References | Top | |||||
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| REF 1 | ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood. 2011 June 30; 117(26): 6999-7006. | |||||
| REF 2 | ClinicalTrials.gov (NCT01620970) PF-03446962 in Relapsed or Refractory Urothelial Cancer. U.S. National Institutes of Health. | |||||
| REF 3 | Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem. 2014 Oct 9;57(19):7900-15. | |||||
| REF 4 | Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52. | |||||
| REF 5 | A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis. 2015 Apr;18(2):209-17. | |||||
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