Target Information
Target General Information | Top | |||||
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Target ID |
T82383
(Former ID: TTDNR00764)
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Target Name |
Tyrosine-protein kinase UFO (AXL)
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Synonyms |
UFO; Tyrosine-protein kinase receptor UFO; AXL oncogene
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Gene Name |
AXL
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
Function |
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.10.1
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Sequence |
MAWRCPRMGRVPLAWCLALCGWACMAPRGTQAEESPFVGNPGNITGARGLTGTLRCQLQV
QGEPPEVHWLRDGQILELADSTQTQVPLGEDEQDDWIVVSQLRITSLQLSDTGQYQCLVF LGHQTFVSQPGYVGLEGLPYFLEEPEDRTVAANTPFNLSCQAQGPPEPVDLLWLQDAVPL ATAPGHGPQRSLHVPGLNKTSSFSCEAHNAKGVTTSRTATITVLPQQPRNLHLVSRQPTE LEVAWTPGLSGIYPLTHCTLQAVLSDDGMGIQAGEPDPPEEPLTSQASVPPHQLRLGSLH PHTPYHIRVACTSSQGPSSWTHWLPVETPEGVPLGPPENISATRNGSQAFVHWQEPRAPL QGTLLGYRLAYQGQDTPEVLMDIGLRQEVTLELQGDGSVSNLTVCVAAYTAAGDGPWSLP VPLEAWRPGQAQPVHQLVKEPSTPAFSWPWWYVLLGAVVAAACVLILALFLVHRRKKETR YGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEELKEKLRDVMVDRHKVALGK TLGEGEFGAVMEGQLNQDDSILKVAVKTMKIAICTRSELEDFLSEAVCMKEFDHPNVMRL IGVCFQGSERESFPAPVVILPFMKHGDLHSFLLYSRLGDQPVYLPTQMLVKFMADIASGM EYLSTKRFIHRDLAARNCMLNENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIES LADRVYTSKSDVWSFGVTMWEIATRGQTPYPGVENSEIYDYLRQGNRLKQPADCLDGLYA LMSRCWELNPQDRPSFTELREDLENTLKALPPAQEPDEILYVNMDEGGGYPEPPGAAGGA DPPTQPDPKDSCSCLTAAEVHPAGRYVLCPSTTPSPAQPADRGSPAAPGQEDGA Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T06ADX |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Gilteritinib | Drug Info | Approved | Acute myeloid leukaemia | [1], [2] | |
Clinical Trial Drug(s) | [+] 16 Clinical Trial Drugs | + | ||||
1 | Bemcentinib | Drug Info | Phase 2 | Non-small-cell lung cancer | [3] | |
2 | BGB-324 | Drug Info | Phase 2 | Breast cancer | [1] | |
3 | BI-505 | Drug Info | Phase 2 | Multiple myeloma | [4] | |
4 | Mecbotamab vedotin | Drug Info | Phase 2 | Soft tissue sarcoma | [5] | |
5 | MGCD265 | Drug Info | Phase 2 | Non-small-cell lung cancer | [6] | |
6 | Enapotamab vedotin | Drug Info | Phase 1/2 | Solid tumour/cancer | [7] | |
7 | ONO-7475 | Drug Info | Phase 1/2 | Myelodysplastic syndrome | [8] | |
8 | TP-0903 | Drug Info | Phase 1/2 | Chronic lymphocytic leukaemia | [9] | |
9 | A416 | Drug Info | Phase 1 | Aggressive cancer | [10] | |
10 | AVB-S6-500 | Drug Info | Phase 1 | Acute myeloid leukaemia | [1] | |
11 | BPI-9016 M | Drug Info | Phase 1 | Solid tumour/cancer | [11] | |
12 | DS-1205 | Drug Info | Phase 1 | Non-small-cell lung cancer | [1] | |
13 | INCB81776 | Drug Info | Phase 1 | Solid tumour/cancer | [12] | |
14 | ONO-7475 | Drug Info | Phase 1 | Acute myeloid leukaemia | [1] | |
15 | PF-07265807 | Drug Info | Phase 1 | Solid tumour/cancer | [13] | |
16 | RXDX-106 | Drug Info | Phase 1 | Solid tumour/cancer | [14] | |
Preclinical Drug(s) | [+] 4 Preclinical Drugs | + | ||||
1 | Cu-anti-hAXL | Drug Info | Preclinical | Breast cancer | [15] | |
2 | DP-3975 | Drug Info | Preclinical | Mesothelioma | [15] | |
3 | GL21.T | Drug Info | Preclinical | Non-small-cell lung cancer | [15] | |
4 | YW327.6S2 | Drug Info | Preclinical | Non-small-cell lung cancer | [15] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 17 Inhibitor drugs | + | ||||
1 | Gilteritinib | Drug Info | [1] | |||
2 | Bemcentinib | Drug Info | [16] | |||
3 | BI-505 | Drug Info | [4] | |||
4 | Mecbotamab vedotin | Drug Info | [5] | |||
5 | Enapotamab vedotin | Drug Info | [19] | |||
6 | ONO-7475 | Drug Info | [20] | |||
7 | TP-0903 | Drug Info | [1] | |||
8 | A416 | Drug Info | [10] | |||
9 | AVB-S6-500 | Drug Info | [1] | |||
10 | BPI-9016 M | Drug Info | [21] | |||
11 | DS-1205 | Drug Info | [1] | |||
12 | INCB81776 | Drug Info | [22] | |||
13 | ONO-7475 | Drug Info | [1] | |||
14 | PF-07265807 | Drug Info | [23] | |||
15 | RXDX-106 | Drug Info | [24] | |||
16 | DP-3975 | Drug Info | [15] | |||
17 | LDC1267 | Drug Info | [26] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | MGCD265 | Drug Info | [18] |
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: (10r)-7-Amino-11-Chloro-12-Fluoro-1-(2-Hydroxyethyl)-3,10,16-Trimethyl-16,17-Dihydro-1h-8,4-(Azeno)pyrazolo[4,3-H][2,5,11]benzoxadiazacyclotetradecin-15(10h)-One | Ligand Info | |||||
Structure Description | Structure of the Axl kinase domain in complex with a macrocyclic inhibitor | PDB:5U6B | ||||
Method | X-ray diffraction | Resolution | 2.84 Å | Mutation | No | [27] |
PDB Sequence |
ELKEKLRDVM
530 VDRHKVALGK540 TLGEGEFGAV550 MEGQLNQDDS560 ILKVAVKTMK570 IAICTRSELE 580 DFLSEAVCMK590 EFDHPNVMRL600 IGVCFQPAPV617 VILPFMKHGD627 LHSFLLYSRL 637 GDQPVYLPTQ647 MLVKFMADIA657 SGMEYLSTKR667 FIHRDLAARN677 CMLNENMSVC 687 VADFGLSKPV713 KWIAIESLAD723 RVYTSKSDVW733 SFGVTMWEIA743 TRGQTPYPGV 753 ENSEIYDYLR763 QGNRLKQPAD773 CLDGLYALMS783 RCWELNPQDR793 PSFTELREDL 803 ENTLKALPPA813
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LEU542
3.528
GLY543
4.030
VAL550
3.324
ALA565
3.296
LYS567
3.819
MET598
3.399
LEU620
3.624
PRO621
2.749
PHE622
3.598
MET623
3.045
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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).
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
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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Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.35E-06 |
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Closeness centrality | 1.64E-01 | Radiality | 1.25E+01 | Clustering coefficient | 0.00E+00 |
Neighborhood connectivity | 3.50E+00 | Topological coefficient | 5.00E-01 | Eccentricity | 14 |
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 |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
1 | FSH Signaling Pathway | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | Validated transcriptional targets of deltaNp63 isoforms | |||||
Reactome | [+] 1 Reactome Pathways | + | ||||
1 | VEGFA-VEGFR2 Pathway | |||||
WikiPathways | [+] 3 WikiPathways | + | ||||
1 | miR-targeted genes in squamous cell - TarBase | |||||
2 | miR-targeted genes in muscle cell - TarBase | |||||
3 | miR-targeted genes in lymphocytes - TarBase |
References | Top | |||||
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REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
REF 3 | ClinicalTrials.gov (NCT03184571) Bemcentinib (BGB324) in Combination With Pembrolizumab in Patients With Advanced NSCLC. U.S. National Institutes of Health. | |||||
REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 5 | Clinical pipeline report, company report or official report of BioAtla | |||||
REF 6 | ClinicalTrials.gov (NCT02544633) Phase 2 Study of MGCD265 in Patients With Non-Small Cell Lung Cancer With Activating Genetic Alterations in MET. | |||||
REF 7 | ClinicalTrials.gov (NCT02988817) Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors. U.S. National Institutes of Health. | |||||
REF 8 | ClinicalTrials.gov (NCT03176277) A Study of ONO-7475 in Patients With Acute Leukemias. U.S. National Institutes of Health. | |||||
REF 9 | ClinicalTrials.gov (NCT03572634) Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL. U.S. National Institutes of Health. | |||||
REF 10 | Clinical pipeline report, company report or official report of Klus Pharma | |||||
REF 11 | ClinicalTrials.gov (NCT02478866) Safety and Pharmacokinetics of BPI-9016M in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
REF 12 | ClinicalTrials.gov (NCT03522142) A Study Exploring the Safety and Tolerability of INCB081776 in Participants With Advanced Malignancies. U.S. National Institutes of Health. | |||||
REF 13 | ClinicalTrials.gov (NCT04458259) A Study of PF-07265807 In Participants With Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health. | |||||
REF 14 | ClinicalTrials.gov (NCT03454243) Oral Immunomodulatory Tyrosine Kinase Inhibitor in Patients With Locally Advanced or Metastatic Solid Tumors (TITAN). U.S. National Institutes of Health. | |||||
REF 15 | AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019 Nov 4;18(1):153. | |||||
REF 16 | AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells. J Thorac Oncol. 2020 Jun;15(6):973-999. | |||||
REF 17 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1835). | |||||
REF 18 | Company report (Mirati Therapeutics: formerly MethylGene) | |||||
REF 19 | Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer. JCI Insight. 2019 Nov 1;4(21):e128199. | |||||
REF 20 | Clinical pipeline report, company report or official report of Ono Pharmaceutical. | |||||
REF 21 | First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer. J Hematol Oncol. 2020 Jan 16;13(1):6. | |||||
REF 22 | A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity. Front Oncol. 2020 Dec 7;10:598477. | |||||
REF 23 | National Cancer Institute Drug Dictionary (drug name PF-07265807). | |||||
REF 24 | National Cancer Institute Drug Dictionary (drug name RXDX106). | |||||
REF 25 | MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer. Contrast Media Mol Imaging. 2017 May 14;2017:1686525. | |||||
REF 26 | The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. | |||||
REF 27 | The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase. J Biol Chem. 2017 Sep 22;292(38):15705-15716. |
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