Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZPY6J)

• DTT Name: Tyrosine-protein kinase UFO (AXL)
• Synonyms: UFO; Tyrosine-protein kinase receptor UFO; AXL oncogene
• Gene Name: AXL
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: UFO_HUMAN
• TTD ID: T82383
• EC Number: EC 2.7.10.1
• Sequence:
  MAWRCPRMGRVPLAWCLALCGWACMAPRGTQAEESPFVGNPGNITGARGLTGTLRCQLQV
  QGEPPEVHWLRDGQILELADSTQTQVPLGEDEQDDWIVVSQLRITSLQLSDTGQYQCLVF
  LGHQTFVSQPGYVGLEGLPYFLEEPEDRTVAANTPFNLSCQAQGPPEPVDLLWLQDAVPL
  ATAPGHGPQRSLHVPGLNKTSSFSCEAHNAKGVTTSRTATITVLPQQPRNLHLVSRQPTE
  LEVAWTPGLSGIYPLTHCTLQAVLSDDGMGIQAGEPDPPEEPLTSQASVPPHQLRLGSLH
  PHTPYHIRVACTSSQGPSSWTHWLPVETPEGVPLGPPENISATRNGSQAFVHWQEPRAPL
  QGTLLGYRLAYQGQDTPEVLMDIGLRQEVTLELQGDGSVSNLTVCVAAYTAAGDGPWSLP
  VPLEAWRPGQAQPVHQLVKEPSTPAFSWPWWYVLLGAVVAAACVLILALFLVHRRKKETR
  YGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEELKEKLRDVMVDRHKVALGK
  TLGEGEFGAVMEGQLNQDDSILKVAVKTMKIAICTRSELEDFLSEAVCMKEFDHPNVMRL
  IGVCFQGSERESFPAPVVILPFMKHGDLHSFLLYSRLGDQPVYLPTQMLVKFMADIASGM
  EYLSTKRFIHRDLAARNCMLNENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIES
  LADRVYTSKSDVWSFGVTMWEIATRGQTPYPGVENSEIYDYLRQGNRLKQPADCLDGLYA
  LMSRCWELNPQDRPSFTELREDLENTLKALPPAQEPDEILYVNMDEGGGYPEPPGAAGGA
  DPPTQPDPKDSCSCLTAAEVHPAGRYVLCPSTTPSPAQPADRGSPAAPGQEDGA
• 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.
• KEGG Pathway: EGFR tyrosine kinase inhibitor resistance (hsa01521)
• Reactome Pathway: VEGFA-VEGFR2 Pathway (R-HSA-4420097)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Gilteritinib	DMTI0ZO	Acute myeloid leukaemia	2A60	Approved	[1]

15 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bemcentinib	DM0YCPL	Myelodysplastic syndrome	2A37	Phase 2	[2]
BGB-324	DMDI43Y	Breast cancer	2C60-2C65	Phase 2	[3]
BI-505	DMSZQHX	Multiple myeloma	2A83	Phase 2	[4]
Mecbotamab vedotin	DMU5KH4	Ovarian cancer	2C73	Phase 2	[5]
MGCD265	DMRPCF2	Non-small-cell lung cancer	2C25.Y	Phase 2	[6]
Enapotamab vedotin	DM1PQJO	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[7]
ONO-7475	DMV6GX7	Acute leukaemia	2A60	Phase 1/2	[1]
TP-0903	DMHTG8P	Chronic lymphocytic leukaemia	2A82.0	Phase 1/2	[1]
A416	DMBQXAX	Aggressive cancer	2A00-2F9Z	Phase 1	[8]
AVB-S6-500	DMKCRMD	Acute myeloid leukaemia	2A60	Phase 1	[1]
BPI-9016 M	DMNY0U5	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
DS-1205	DMXST9F	Non-small-cell lung cancer	2C25.Y	Phase 1	[1]
INCB81776	DMFOXGB	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
PF-07265807	DMSMNRQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
RXDX-106	DM6NVTR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]

4 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cu-anti-hAXL	DMKVW25	Breast cancer	2C60-2C65	Preclinical	[13]
DP-3975	DMYH3VR	Mesothelioma	2C51.2	Preclinical	[14]
GL21.T	DMZC91G	Non-small-cell lung cancer	2C25.Y	Preclinical	[14]
YW327.6S2	DMH0I9N	Breast cancer	2C60-2C65	Preclinical	[14]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LDC1267	DMH7R6L	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	1.13E-65	-0.53	-2.04

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells. J Thorac Oncol. 2020 Jun;15(6):973-999.
• [3] 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).
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Clinical pipeline report, company report or official report of BioAtla
• [6] Company report (Mirati Therapeutics: formerly MethylGene)
• [7] 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.
• [8] Clinical pipeline report, company report or official report of Klus Pharma
• [9] 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.
• [10] A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity. Front Oncol. 2020 Dec 7;10:598477.
• [11] National Cancer Institute Drug Dictionary (drug name PF-07265807).
• [12] National Cancer Institute Drug Dictionary (drug name RXDX106).
• [13] MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer. Contrast Media Mol Imaging. 2017 May 14;2017:1686525.
• [14] AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019 Nov 4;18(1):153.
• [15] The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12.