AXL receptor tyrosine kinase | Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

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AXL receptor tyrosine kinase

Target id: 1835

Nomenclature: AXL receptor tyrosine kinase

Abbreviated Name: Axl

Family: Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     AXL receptor tyrosine kinase has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 885 19q13.1 AXL AXL receptor tyrosine kinase
Mouse 1 888 7 A3-B1 Axl AXL receptor tyrosine kinase
Rat - 888 1q21 Axl Axl receptor tyrosine kinase
Previous and Unofficial Names
tyrosine-protein kinase receptor UFO | Ark | Tyro7
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of a minimal Gas6-Axl complex
PDB Id:  2C5D
Resolution:  3.3Å
Species:  Human
References:  10
Enzyme Reaction
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
BMS-777607 Hs Inhibition 9.0 pIC50 11
pIC50 9.0 (IC50 1.1x10-9 M) [11]
sitravatinib Hs Inhibition 8.8 pIC50 9
pIC50 8.8 (IC50 1.5x10-9 M) [9]
Description: In a biochemical enzyme activity assay.
merestinib Hs Inhibition 8.0 pIC50 13
pIC50 8.0 (IC50 1.1x10-8 M) [13]
Description: Inhibition of in vitro biochemical activity by EMD Millipore assay.
TP-0903 Hs Inhibition 7.6 pIC50 7
pIC50 7.6 (IC50 2.7x10-8 M) [7]
LDC1267 Hs Inhibition 7.5 pIC50 8
pIC50 7.5 (IC50 2.9x10-8 M) [8]
Inhibitor Comments
Aravive-S6 (MYD1-A72V, MYD1-72) is a preclinical, engineered fusion protein that acts as a soluble AXL decoy receptor, designed to overcome the potent binding between AXL and its endogenous ligand growth arrest specific protein 6 (GAS6) [2]. Structurally it is a fusion of AXL (with an Ala72Val substitution) and human IgG1 Fc. The affinity of this fusion vs. GAS6 is ~0.09pM (the AXL-GAS6 affinity is around 30pM) [6]. MYD1-A72V is reported to improve the efficiency of chemotherapies in preclinical models [6].
Antibody Comments
Genmab have an anti-AXL antibody-drug conjugate (HuMax-AXL-ADC, enapotamab vedotin) in their oncology developent pipeline. The ADC delivers a toxic monomethyl auristatin E (MMAE, a microtubule disrupting agent) payload to targeted cancer cells. Phase 1/2 trial NCT02988817 is evaluating HuMax-AXL-ADC in several types of solid tumours.
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 3,12

Key to terms and symbols Click column headers to sort
Target used in screen: AXL
Ligand Sp. Type Action Affinity Units
foretinib Hs Inhibitor Inhibition 10.0 pKd
JNJ-28312141 Hs Inhibitor Inhibition 8.3 pKd
staurosporine Hs Inhibitor Inhibition 8.2 pKd
crizotinib Hs Inhibitor Inhibition 8.1 pKd
sunitinib Hs Inhibitor Inhibition 8.1 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.9 pKd
lestaurtinib Hs Inhibitor Inhibition 7.5 pKd
bosutinib Hs Inhibitor Inhibition 7.3 pKd
tamatinib Hs Inhibitor Inhibition 7.1 pKd
SU-14813 Hs Inhibitor Inhibition 7.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,4

Key to terms and symbols Click column headers to sort
Target used in screen: Axl/AXL
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 10.3 81.0 42.0
staurosporine Hs Inhibitor Inhibition 13.3 3.0 0.0
SU11652 Hs Inhibitor Inhibition 25.2 9.0 1.0
sunitinib Hs Inhibitor Inhibition 27.4
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 34.2 3.0 2.0
bosutinib Hs Inhibitor Inhibition 37.6
SB 218078 Hs Inhibitor Inhibition 38.1 91.0 87.0
SU6656 Hs Inhibitor Inhibition 39.7 51.0 36.0
K-252a Hs Inhibitor Inhibition 41.0 4.0 -3.0
indirubin derivative E804 Hs Inhibitor Inhibition 42.7 12.0 5.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
All three TAM family receptor tyrosine kinases are involved in regulating inflammatory responses through a negative feedback loop. Specifically, AXL-Gas6 signalling is reported to induce autophagy in murine macrophages via inhibition of the NLRP3 inflammasome, an effect which reduces hepatic inflammation in a mouse model [5].
Immuno Process Associations
Immuno Process:  Barrier integrity
GO Annotations:  Associated to 2 GO processes
GO:0046718 viral entry into host cell IMP
click arrow to show/hide IEA associations
GO:0001618 virus receptor activity IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 5 GO processes
GO:0006909 phagocytosis IDA
click arrow to show/hide IEA associations
GO:0006954 inflammatory response IEA
GO:0043277 apoptotic cell clearance IEA
GO:0045087 innate immune response IEA
GO:0097350 neutrophil clearance IEA
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 4 GO processes
GO:0006909 phagocytosis IDA
GO:0048549 positive regulation of pinocytosis IMP
click arrow to show/hide IEA associations
GO:0043277 apoptotic cell clearance IEA
GO:0097350 neutrophil clearance IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0032825 positive regulation of natural killer cell differentiation IDA
click arrow to show/hide IEA associations
GO:0034101 erythrocyte homeostasis IEA
GO:0051250 negative regulation of lymphocyte activation IEA
GO:0097350 neutrophil clearance IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 3 GO processes
GO:0032825 positive regulation of natural killer cell differentiation IDA
GO:0097028 dendritic cell differentiation IEP
click arrow to show/hide IEA associations
GO:0001779 natural killer cell differentiation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 4 GO processes
GO:0001961 positive regulation of cytokine-mediated signaling pathway IDA
GO:0032689 negative regulation of interferon-gamma production IDA
GO:0035457 cellular response to interferon-alpha IDA
click arrow to show/hide IEA associations
GO:0032720 negative regulation of tumor necrosis factor production IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 3 GO processes
GO:0032825 positive regulation of natural killer cell differentiation IDA
click arrow to show/hide IEA associations
GO:0001779 natural killer cell differentiation IEA
GO:0051250 negative regulation of lymphocyte activation IEA

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Cochran JR, Goaccia AJ, Miao Y, Kariolis M, Kapur S, Mathews II. (2015) High-affinity binding to gas6. Patent number: WO2015030849. Assignee: The Board Of Trustees Of The Leland Stanford Junior University. Priority date: 30/08/2013. Publication date: 05/03/2015.

3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

4. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

5. Han J, Bae J, Choi CY, Choi SP, Kang HS, Jo EK, Park J, Lee YS, Moon HS, Park CG et al.. (2016) Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. Autophagy, 12 (12): 2326-2343. [PMID:27780404]

6. Kariolis MS, Miao YR, Diep A, Nash SE, Olcina MM, Jiang D, Jones 2nd DS, Kapur S, Mathews II, Koong AC et al.. (2017) Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. J. Clin. Invest., 127 (1): 183-198. [PMID:27893463]

7. Mollard A, Warner SL, Call LT, Wade ML, Bearss JJ, Verma A, Sharma S, Vankayalapati H, Bearss DJ. (2011) Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. ACS Med Chem Lett, 2 (12): 907-912. [PMID:22247788]

8. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP et al.. (2014) The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature, 507 (7493): 508-12. [PMID:24553136]

9. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. (2016) Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget, 7 (4): 4093-109. [PMID:26675259]

10. Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Göhring W, Ullrich A, Timpl R, Hohenester E. (2006) Structural basis for Gas6-Axl signalling. EMBO J., 25 (1): 80-7. [PMID:16362042]

11. Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B et al.. (2009) Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem., 52 (5): 1251-4. [PMID:19260711]

12. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

13. Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR et al.. (2013) LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs, 31 (4): 833-44. [PMID:23275061]

How to cite this page

Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family: AXL receptor tyrosine kinase. Last modified on 24/04/2018. Accessed on 20/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1835.