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Target has curated data in GtoImmuPdb
Target id: 1835
Nomenclature: AXL receptor tyrosine kinase
Abbreviated Name: Axl
Family: Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family
Gene and Protein Information | ||||||
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 |
Anexelekto | Ark | Tyro7 | tyrosine-protein kinase receptor UFO |
Database Links | |
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 | |||||||||||
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Enzyme Reaction | ||||
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Natural/Endogenous Ligands |
growth arrest specific protein 6 {Sp: Human} |
protein S {Sp: Human} |
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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
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Target used in screen: AXL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 1,7 |
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Target used in screen: Axl/AXL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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. |
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). |
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]
Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family: AXL receptor tyrosine kinase. Last modified on 02/04/2024. Accessed on 04/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1835.