Target Information
Target General Information | Top | |||||
---|---|---|---|---|---|---|
Target ID |
T82383
(Former ID: TTDNR00764)
|
|||||
Target Name |
Tyrosine-protein kinase UFO (AXL)
|
|||||
Synonyms |
UFO; Tyrosine-protein kinase receptor UFO; AXL oncogene
|
|||||
Gene Name |
AXL
|
|||||
Target Type |
Successful target
|
[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.
Click to Show/Hide
|
|||||
BioChemical Class |
Kinase
|
|||||
UniProt ID | ||||||
EC Number |
EC 2.7.10.1
|
|||||
Sequence |
MAWRCPRMGRVPLAWCLALCGWACMAPRGTQAEESPFVGNPGNITGARGLTGTLRCQLQV
QGEPPEVHWLRDGQILELADSTQTQVPLGEDEQDDWIVVSQLRITSLQLSDTGQYQCLVF LGHQTFVSQPGYVGLEGLPYFLEEPEDRTVAANTPFNLSCQAQGPPEPVDLLWLQDAVPL ATAPGHGPQRSLHVPGLNKTSSFSCEAHNAKGVTTSRTATITVLPQQPRNLHLVSRQPTE LEVAWTPGLSGIYPLTHCTLQAVLSDDGMGIQAGEPDPPEEPLTSQASVPPHQLRLGSLH PHTPYHIRVACTSSQGPSSWTHWLPVETPEGVPLGPPENISATRNGSQAFVHWQEPRAPL QGTLLGYRLAYQGQDTPEVLMDIGLRQEVTLELQGDGSVSNLTVCVAAYTAAGDGPWSLP VPLEAWRPGQAQPVHQLVKEPSTPAFSWPWWYVLLGAVVAAACVLILALFLVHRRKKETR YGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEELKEKLRDVMVDRHKVALGK TLGEGEFGAVMEGQLNQDDSILKVAVKTMKIAICTRSELEDFLSEAVCMKEFDHPNVMRL IGVCFQGSERESFPAPVVILPFMKHGDLHSFLLYSRLGDQPVYLPTQMLVKFMADIASGM EYLSTKRFIHRDLAARNCMLNENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIES LADRVYTSKSDVWSFGVTMWEIATRGQTPYPGVENSEIYDYLRQGNRLKQPADCLDGLYA LMSRCWELNPQDRPSFTELREDLENTLKALPPAQEPDEILYVNMDEGGGYPEPPGAAGGA DPPTQPDPKDSCSCLTAAEVHPAGRYVLCPSTTPSPAQPADRGSPAAPGQEDGA Click to Show/Hide
|
|||||
3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T06ADX |
Drugs and Modes of Action | Top | |||||
---|---|---|---|---|---|---|
Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Gilteritinib | Drug Info | Approved | Acute myeloid leukaemia | [1], [2] | |
Clinical Trial Drug(s) | [+] 14 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 | MGCD265 | Drug Info | Phase 2 | Non-small-cell lung cancer | [5] | |
5 | Enapotamab vedotin | Drug Info | Phase 1/2 | Solid tumour/cancer | [6] | |
6 | ONO-7475 | Drug Info | Phase 1/2 | Myelodysplastic syndrome | [7] | |
7 | TP-0903 | Drug Info | Phase 1/2 | Chronic lymphocytic leukaemia | [8] | |
8 | AVB-S6-500 | Drug Info | Phase 1 | Acute myeloid leukaemia | [1] | |
9 | BPI-9016 M | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
10 | DS-1205 | Drug Info | Phase 1 | Non-small-cell lung cancer | [1] | |
11 | INCB81776 | Drug Info | Phase 1 | Solid tumour/cancer | [10] | |
12 | ONO-7475 | Drug Info | Phase 1 | Acute myeloid leukaemia | [1] | |
13 | PF-07265807 | Drug Info | Phase 1 | Solid tumour/cancer | [11] | |
14 | RXDX-106 | Drug Info | Phase 1 | Solid tumour/cancer | [12] | |
Preclinical Drug(s) | [+] 4 Preclinical Drugs | + | ||||
1 | Cu-anti-hAXL | Drug Info | Preclinical | Breast cancer | [13] | |
2 | DP-3975 | Drug Info | Preclinical | Mesothelioma | [13] | |
3 | GL21.T | Drug Info | Preclinical | Non-small-cell lung cancer | [13] | |
4 | YW327.6S2 | Drug Info | Preclinical | Non-small-cell lung cancer | [13] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 15 Inhibitor drugs | + | ||||
1 | Gilteritinib | Drug Info | [1] | |||
2 | Bemcentinib | Drug Info | [14] | |||
3 | BI-505 | Drug Info | [4] | |||
4 | Enapotamab vedotin | Drug Info | [17] | |||
5 | ONO-7475 | Drug Info | [18] | |||
6 | TP-0903 | Drug Info | [1] | |||
7 | AVB-S6-500 | Drug Info | [1] | |||
8 | BPI-9016 M | Drug Info | [19] | |||
9 | DS-1205 | Drug Info | [1] | |||
10 | INCB81776 | Drug Info | [20] | |||
11 | ONO-7475 | Drug Info | [1] | |||
12 | PF-07265807 | Drug Info | [21] | |||
13 | RXDX-106 | Drug Info | [22] | |||
14 | DP-3975 | Drug Info | [13] | |||
15 | LDC1267 | Drug Info | [24] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | MGCD265 | Drug Info | [16] |
Chemical Structure based Activity Landscape of Target | Top |
---|---|
Drug Property Profile of Target | Top | |
---|---|---|
(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
||
(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
||
(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
||
"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 | |||||
---|---|---|---|---|---|---|
Co-Targets |
Target Poor or Non Binders | Top | |||||
---|---|---|---|---|---|---|
Target Poor or Non Binders |
Target Regulators | Top | |||||
---|---|---|---|---|---|---|
Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
---|---|---|---|---|---|---|
Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
---|---|---|---|---|---|---|
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 | |||||
---|---|---|---|---|---|---|
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 | ClinicalTrials.gov (NCT02544633) Phase 2 Study of MGCD265 in Patients With Non-Small Cell Lung Cancer With Activating Genetic Alterations in MET. | |||||
REF 6 | ClinicalTrials.gov (NCT02988817) Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors. U.S. National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT03176277) A Study of ONO-7475 in Patients With Acute Leukemias. U.S. National Institutes of Health. | |||||
REF 8 | 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 9 | ClinicalTrials.gov (NCT02478866) Safety and Pharmacokinetics of BPI-9016M in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
REF 10 | ClinicalTrials.gov (NCT03522142) A Study Exploring the Safety and Tolerability of INCB081776 in Participants With Advanced Malignancies. U.S. National Institutes of Health. | |||||
REF 11 | ClinicalTrials.gov (NCT04458259) A Study of PF-07265807 In Participants With Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health. | |||||
REF 12 | 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 13 | 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 14 | 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 15 | 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 16 | Company report (Mirati Therapeutics: formerly MethylGene) | |||||
REF 17 | 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 18 | Clinical pipeline report, company report or official report of Ono Pharmaceutical. | |||||
REF 19 | 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 20 | 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 21 | National Cancer Institute Drug Dictionary (drug name PF-07265807). | |||||
REF 22 | National Cancer Institute Drug Dictionary (drug name RXDX106). | |||||
REF 23 | MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer. Contrast Media Mol Imaging. 2017 May 14;2017:1686525. | |||||
REF 24 | The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. |
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.