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MER proto-oncogene, tyrosine kinase

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Target id: 1837

Nomenclature: MER proto-oncogene, tyrosine kinase

Abbreviated Name: Mer

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 1 999 2q13 MERTK MER proto-oncogene, tyrosine kinase
Mouse 1 994 2 F1 Mertk MER proto-oncogene tyrosine kinase
Rat 1 994 3q36 Mertk MER proto-oncogene, tyrosine kinase
Previous and Unofficial Names Click here for help
RP38 | Rdy | retinal dystrophy | tyrosine-protein kinase Mer | Eyk | Nyk | Tyro 12 | c-mer proto-oncogene tyrosine kinase | MER proto-oncogene
Database Links Click here for help
Alphafold Q12866 (Hs), Q60805 (Mm), P57097 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.40.10
ChEMBL Target CHEMBL5331 (Hs), CHEMBL4879469 (Mm)
Ensembl Gene ENSG00000153208 (Hs), ENSMUSG00000014361 (Mm), ENSRNOG00000017319 (Rn)
Entrez Gene 10461 (Hs), 17289 (Mm), 65037 (Rn)
Human Protein Atlas ENSG00000153208 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:10461 (Hs), mmu:17289 (Mm), rno:65037 (Rn)
OMIM 604705 (Hs)
Orphanet ORPHA123198 (Hs)
Pharos Q12866 (Hs)
RefSeq Nucleotide NM_006343 (Hs), NM_008587 (Mm), NM_022943 (Rn)
RefSeq Protein NP_006334 (Hs), NP_032613 (Mm), NP_075232 (Rn)
UniProtKB Q12866 (Hs), Q60805 (Mm), P57097 (Rn)
Wikipedia MERTK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with ADP
PDB Id:  3BRB
Ligand:  ADP   This ligand is endogenous
Resolution:  1.9Å
Species:  Human
References:  8
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}

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
merestinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.1 pKd 22
⤷ pKd 9.1 (Kd 8x10-10 M) [22]
Description: Binding constant determined by KINOMEScan assay.
belizatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pKd 11
⤷ pKd 7.7 (Kd 1.8x10-8 M) [11]
Description: Binding affinity in vitro.
adrixetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >7.0 pKd 13
⤷ pKd >7.0 (Kd <1x10-7 M) [13]
UNC4203 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.4 pKi 24
⤷ pKi 9.4 (Ki 4.3x10-10 M) [24]
metatinib Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.7 pKi 2
⤷ pKi 7.7 (Ki 2.24x10-8 M) [2]
denfivontinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 9
⤷ pIC50 9.0 (IC50 1x10-9 M) [9]
sitravatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 16
⤷ pIC50 8.7 (IC50 2x10-9 M) [16]
Description: In a biochemical enzyme activity assay.
gilteritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition ~8.5 pIC50 10
⤷ pIC50 ~8.5 (IC50 ~3x10-9 M) [10]
LDC1267 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 15
⤷ pIC50 8.3 (IC50 5x10-9 M) [15]
zanzalintinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.0 pIC50 3
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [3]
Description: Inhibition of substrate phosphorylation by hMER (residues R557-E882 with H628Q and R794A) in vitro
BMS-777607 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pIC50 18
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [18]
MK-2461 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 14
⤷ pIC50 7.6 (IC50 2.4x10-8 M) [14]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 12
⤷ pIC50 7.5 (IC50 2.9x10-8 M) [12]
pIC50 7.5 (IC50 2.9x10-8 M) [12]
metatinib Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.9 pIC50 2
⤷ pIC50 6.9 (IC50 1.299x10-7 M) [2]
Description: Inhibition at intracellular ATP concentration of 1 mM
SLC-391 Small molecule or natural product Click here for species-specific activity table Hs Inhibition >6.3 pIC50 23
⤷ pIC50 >6.3 (IC50 <5x10-7 M) [23]
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: 5,21
Key to terms and symbols Click column headers to sort
Target used in screen: MERTK
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.6 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.2 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.2 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.0 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 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: 1,6
Key to terms and symbols Click column headers to sort
Target used in screen: Mer/c-MER
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.6 2.0 0.5
K-252a Small molecule or natural product Hs Inhibitor Inhibition 3.6 2.0 0.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 11.5 7.0 0.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 13.6 34.0 11.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 14.8 -1.0 -1.0
EGFR/ErbB-2 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 19.5 64.0 49.0
SU6656 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 20.9 12.0 13.0
SU11274 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 21.4 1.0 1.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 28.9
PDGF RTK inhibitor Small molecule or natural product Hs Inhibitor Inhibition 32.3 14.0 4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Mer plays a critical role in regulating self-tolerance mediated between apoptotic cells, dendritic cells, and T cells [4,20].
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   mature NK T cell (CL:0000814)
References:  4
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
References:  4,15
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
Comment:  Mouse splenic macrophages, marginal zone macrophages, by immunofluorescence staining (Shao et al. 2009); mouse, mature tissue macrophages by mRNA expression (Gautier et al. 2012); mouse dendritic cells (Wallet et al. 2008, Rothlin et al. 2007)
References:  7,19
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  17,20
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Retinitis pigmentosa 38; RP38
Synonyms: Retinitis pigmentosa [Orphanet: ORPHA791] [Disease Ontology: DOID:10584]
Disease Ontology: DOID:10584
OMIM: 613862
Orphanet: ORPHA791

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. Bae SH, Kim JH, Park TH, Lee K, Lee BI, Jang H. (2022) BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity. Exp Mol Med, 54 (9): 1450-1460. [PMID:36056187]

3. 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.

4. Behrens EM, Gadue P, Gong SY, Garrett S, Stein PL, Cohen PL. (2003) The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity. Eur J Immunol, 33 (8): 2160-7. [PMID:12884290]

5. 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]

6. 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]

7. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S et al.. (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol, 13 (11): 1118-28. [PMID:23023392]

8. Huang X, Finerty P, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S. (2009) Structural insights into the inhibited states of the Mer receptor tyrosine kinase. J Struct Biol, 165 (2): 88-96. [PMID:19028587]

9. Lee HK, Kim HW, Lee IY, Lee J, Lee J, Jung DS, Lee SY, Park SH, Hwang H, Choi JS et al.. (2014) G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. Blood, 123 (14): 2209-19. [PMID:24532805]

10. 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]

11. 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]

12. 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]

13. 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.

14. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H et al.. (2010) MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res, 70 (4): 1524-33. [PMID:20145145]

15. 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]

16. 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]

17. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell, 131 (6): 1124-36. [PMID:18083102]

18. 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]

19. Shao WH, Zhen Y, Eisenberg RA, Cohen PL. (2009) The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. Clin Immunol, 133 (1): 138-44. [PMID:19631584]

20. Wallet MA, Sen P, Flores RR, Wang Y, Yi Z, Huang Y, Mathews CE, Earp HS, Matsushima G, Wang B et al.. (2008) MerTK is required for apoptotic cell-induced T cell tolerance. J Exp Med, 205 (1): 219-32. [PMID:18195070]

21. 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]

22. 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]

23. 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.

24. 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: MER proto-oncogene, tyrosine kinase. Last modified on 19/04/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1837.