Top ▲

AXL receptor tyrosine kinase

Click here for help

Target id: 1835

Nomenclature: AXL receptor tyrosine kinase

Abbreviated Name: Axl

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

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 894 19q13.2 AXL AXL receptor tyrosine kinase
Mouse 1 888 7 14.02 cM Axl AXL receptor tyrosine kinase
Rat - 888 1q21 Axl Axl receptor tyrosine kinase
Previous and Unofficial Names Click here for help
Anexelekto | Ark | Tyro7 | tyrosine-protein kinase receptor UFO
Database Links Click here for help
Alphafold P30530 (Hs), Q00993 (Mm)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.40.10
ChEMBL Target CHEMBL4895 (Hs), CHEMBL4879451 (Mm)
Ensembl Gene ENSG00000167601 (Hs), ENSMUSG00000002602 (Mm), ENSRNOG00000020716 (Rn)
Entrez Gene 558 (Hs), 26362 (Mm), 308444 (Rn)
Human Protein Atlas ENSG00000167601 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:558 (Hs), mmu:26362 (Mm), rno:308444 (Rn)
OMIM 109135 (Hs)
Pharos P30530 (Hs)
RefSeq Nucleotide NM_001699 (Hs), NM_009465 (Mm), NM_031794 (Rn)
RefSeq Protein NP_001690 (Hs), NP_033491 (Mm), NP_001177903 (Mm), NP_113982 (Rn)
UniProtKB P30530 (Hs), Q00993 (Mm)
Wikipedia AXL (Hs)
Selected 3D Structures Click here for help
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:  20
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
growth arrest specific protein 6 {Sp: Human}
protein S {Sp: Human}

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 6li [Chan et al., 2022] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.6 pKd 3
⤷ pKd 9.6 (Kd 2.6x10-10 M) [3]
Description: Binding affinity for hAXL
belizatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pKd 13
⤷ pKd 7.5 (Kd 2.9x10-8 M) [13]
Description: Binding affinity in vitro.
adrixetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >7.0 pKd 16
⤷ pKd >7.0 (Kd <1x10-7 M) [16]
UNC4203 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pKi 29
⤷ pKi 7.4 (Ki 4.022x10-8 M) [29]
canlitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.6 pIC50 22
⤷ pIC50 9.6 (IC50 2.4x10-10 M) [22]
gilteritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition ~9.1 pIC50 12
⤷ pIC50 ~9.1 (IC50 ~8x10-10 M) [12]
BMS-777607 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 21
⤷ pIC50 9.0 (IC50 1.1x10-9 M) [21]
sitravatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.8 pIC50 18
⤷ pIC50 8.8 (IC50 1.5x10-9 M) [18]
Description: In a biochemical enzyme activity assay.
compound 6li [Chan et al., 2022] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.8 pIC50 3
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [3]
Description: Inhibition of kinase activity
compound 8i [PMID: 22765894] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 27
⤷ pIC50 8.3 (IC50 4.6x10-9 M) [27]
UNC8969 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 11
⤷ pIC50 8.3 (IC50 5.3x10-9 M) [11]
zanzalintinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.0 pIC50 2
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [2]
Description: Inhibition of hAxl kinase (residues H473-A894 with Q764R) activity in vitro
merestinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 26
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [26]
Description: Inhibition of in vitro biochemical activity by EMD Millipore assay.
ningetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 25
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [25]
bemcentinib Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.8 pIC50 9
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [9]
dubermatinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.6 pIC50 15
⤷ pIC50 7.6 (IC50 2.7x10-8 M) [15]
LDC1267 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 17
⤷ pIC50 7.5 (IC50 2.9x10-8 M) [17]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 14
⤷ pIC50 7.5 (IC50 3.5x10-8 M) [14]
compound 19a [PMID: 30503936] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 19
⤷ pIC50 7.3 (IC50 5.3x10-8 M) [19]
SLC-391 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.0 – 6.3 pIC50 28
⤷ pIC50 6.0 – 6.3 (IC50 1x10-6 – 5x10-7 M) [28]
compound 1 [Cruz-López et al., 2019] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 4.9 pIC50 5
⤷ pIC50 4.9 (IC50 1.3x10-5 M) [5]
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) [4]. 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) [10]. MYD1-A72V is reported to improve the efficiency of chemotherapies in preclinical models [10].
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. The INN tilvestamab has been requested for another anti-AXL monoclonal (INN proposed list 121, August 2019), although the developer is unclear at this time.
DiscoveRx KINOMEscan® screen Click here for help
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: 6,24
Key to terms and symbols Click column headers to sort
Target used in screen: AXL
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 10.0 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 8.3 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.2 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.1 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.1 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
SU-14813 Small molecule or natural product 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 Click here for help
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: 1,7
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 Small molecule or natural product Hs Inhibitor Inhibition 10.3 81.0 42.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 13.3 3.0 0.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 25.2 9.0 1.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 27.4
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 34.2 3.0 2.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 37.6
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 38.1 91.0 87.0
SU6656 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 39.7 51.0 36.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 41.0 4.0 -3.0
indirubin derivative E804 Small molecule or natural product 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 [8].
This protein contains an immunoglobulin (Ig)-like domain that resembles the antibody variable domain, that has been coined the 'V-set domain'. The genes for all human V-set domain containing proteins are listed in HGNC gene group 590.
Immuno Process Associations
Immuno Process:  Barrier integrity
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
General Comments
AXL has been suggested as providing an infection route for SARS-CoV-2 entry into pulmonary and bronchial epithelial cells, that is independent of the well established ACE2-mediated entry system [23]. Like ACE2-mediated infection, AXL also relys on interaction with the virus' spike protein, but the interaction occurs within the spike protein's N terminal domain, rather than with the highly studied ACE2 receptor binding domain (RBD).

References

Show »

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. Bannen LC, Bui M, Jiang F, Tso K, Wang Y, Xu W. (2019) Compounds for the treatment of kinase-dependent disorders. Patent number: WO2019148044A1. Assignee: Exelixis, Inc.. Priority date: 26/01/2018. Publication date: 01/08/2019.

3. Chan S, Zhang Y, Wang J, Yu Q, Peng X, Zou J, Zhou L, Tan L, Duan Y, Zhou Y et al.. (2022) Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors. Journal of Nedicinal Chemistry,. DOI: 10.1021/acs.jmedchem.2c01346

4. 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.

5. Cruz-López O, Temps C, Longo B, Myers SH, Franco-Montalban F, Unciti-Broceta A. (2019) Synthesis and Characterization of a Click-Assembled 18-Atom Macrocycle That Displays Selective AXL Kinase Inhibitory Activity. ACS Omega, 4 (25): 21620-21626. DOI: 10.1021/acsomega.9b03525 [PMID:31867559]

6. 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]

7. 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]

8. 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]

9. Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ et al.. (2010) R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res, 70 (4): 1544-54. [PMID:20145120]

10. 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]

11. Kong D, Tian Q, Chen Z, Zheng H, Stashko MA, Yan D, Earp HS, Frye SV, DeRyckere D, Kireev D et al.. (2024) Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors. J Med Chem, 67 (7): 5866-5882. [PMID:38556760]

12. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 129 (2): 257-260. [PMID:27908881]

13. Lewis RT, Bode CM, Choquette DM, Potashman M, Romero K, Stellwagen JC, Teffera Y, Moore E, Whittington DA, Chen H et al.. (2012) The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer. J Med Chem, 55 (14): 6523-40. [PMID:22734674]

14. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J Med Chem, 61 (24): 11398-11414. [PMID:30480444]

15. 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]

16. Nam K, Kim J, Park D, Jeon Y, Yang YI, Kang HK. (2021) Quinoline derivatives as inhibitors of axl/mer rtk and csf1r. Patent number: US20210163448A1. Assignee: QURIENT CO Ltd. Priority date: 31/05/2019. Publication date: 03/06/2021.

17. 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]

18. 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]

19. Qi B, Yang Y, Gong G, He H, Yue X, Xu X, Hu Y, Li J, Chen T, Wan X et al.. (2019) Discovery of N1-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-N3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea as a multi-tyrosine kinase inhibitor for drug-sensitive and drug-resistant cancers treatment. Eur J Med Chem, 163: 10-27. [PMID:30503936]

20. 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]

21. 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]

22. Sun X, Wang L, Yang H, Hu H. (2020) Crystal forms of compound, preparation method therefor, pharmaceutical composition and application thereof. Patent number: WO2020216188. Assignee: Beijing Kangchen Pharmaceutical Co., Ltd.. Priority date: 20/04/2020. Publication date: 29/10/2020.

23. Wang S, Qiu Z, Hou Y, Deng X, Xu W, Zheng T, Wu P, Xie S, Bian W, Zhang C et al.. (2021) AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res, 31 (2): 126-140. [PMID:33420426]

24. 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]

25. Xi N. (2015) Substituted quinoline compounds and methods of use. Patent number: US9133162B2. Assignee: Sunshine Lake Pharma Co Ltd, Calitor Sciences LLC. Priority date: 28/02/2011. Publication date: 15/09/2015.

26. 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]

27. You WK, Sennino B, Williamson CW, Falcón B, Hashizume H, Yao LC, Aftab DT, McDonald DM. (2011) VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res, 71 (14): 4758-68. [PMID:21613405]

28. Zhang Z. (2015) Aminopyridine derivatives as tam family kinase inhibitors. Patent number: WO2015081257A2. Assignee: Signalchem Lifesciences Corporation. Priority date: 26/11/2014. Publication date: 04/06/2015.

29. Zhao J, Zhang D, Zhang W, Stashko MA, DeRyckere D, Vasileiadi E, Parker RE, Hunter D, Liu Q, Zhang Y et al.. (2018) Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group. J Med Chem, 61 (22): 10242-10254. [PMID:30347155]

How to cite this page

Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family: AXL receptor tyrosine kinase. Last modified on 02/04/2024. Accessed on 10/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1835.