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mechanistic target of rapamycin kinase

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Target id: 2109

Nomenclature: mechanistic target of rapamycin kinase

Abbreviated Name: mTOR

Family: FRAP subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 2549 1p36.22 MTOR mechanistic target of rapamycin kinase
Mouse - 2549 4 78.76 cM Mtor mechanistic target of rapamycin kinase
Rat - 2549 5q36 Mtor mechanistic target of rapamycin kinase
Previous and Unofficial Names Click here for help
FK506 binding protein 12-rapamycin associated protein 2 | FKBP12-rapamycin complex-associated protein 1 | FKBP-rapamycin associated protein | FKBP-rapamycin-associated protein FRAP | RAFT1 | rapamycin and FKBP12 target 1 | rapamycin associated protein FRAP2 | rapamycin target protein 1 | RAPT1 | mammalian target of rapamycin | FK506 binding protein 12-rapamycin associated protein 1 | mechanistic target of rapamycin (serine/threonine kinase) | mechanistic target of rapamycin
Database Links Click here for help
Alphafold P42345 (Hs), Q9JLN9 (Mm), P42346 (Rn)
BRENDA 2.7.11.1
CATH/Gene3D 1.10.1070.11, 1.20.120.150, 1.25.10.10
ChEMBL Target CHEMBL2842 (Hs), CHEMBL1255165 (Mm), CHEMBL1075134 (Rn)
DrugBank Target P42345 (Hs)
Ensembl Gene ENSG00000198793 (Hs), ENSMUSG00000028991 (Mm), ENSRNOG00000009615 (Rn)
Entrez Gene 2475 (Hs), 56717 (Mm), 56718 (Rn)
Human Protein Atlas ENSG00000198793 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:2475 (Hs), mmu:56717 (Mm), rno:56718 (Rn)
OMIM 601231 (Hs)
Pharos P42345 (Hs)
RefSeq Nucleotide NM_004958 (Hs), NM_020009 (Mm), NM_019906 (Rn)
RefSeq Protein NP_004949 (Hs), NP_064393 (Mm), NP_063971 (Rn)
SynPHARM 82830 (in complex with compound 82 [PMID: 21332118])
80974 (in complex with PI-103)
81767 (in complex with PP-242)
82891 (in complex with torin 2)
UniProtKB P42345 (Hs), Q9JLN9 (Mm), P42346 (Rn)
Wikipedia MTOR (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Co-crystal structure of the PPIase domain of FKBP51, Rapamycin and the FRB fragment of mTOR
PDB Id:  4DRI
Resolution:  1.45Å
Species:  Human
References:  29
Image of receptor 3D structure from RCSB PDB
Description:  The solution structure of the rapamycin-binding domain of mTOR (FRB)
PDB Id:  2NPU
Resolution:  0.0Å
Species:  Human
References:  41
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of PI3K-gamma in complex with benzothiazole 82.
PDB Id:  3QK0
Ligand:  compound 82 [PMID: 21332118]
Resolution:  2.85Å
Species:  Human
References:  8
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

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
PQR620 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.6 pKd 32
⤷ pKd 9.6 (Kd 2.7x10-10 M) [32]
Description: Binding affinity constant.
neolymphostin A Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pKd 7
⤷ pKd 8.0 (Kd 1x10-8 M) [7]
Description: Determined using an active-site dependent competition binding assay.
bimiralisib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.9 pKd
⤷ pKd 7.9 (Kd 1.2x10-8 M)
compound 12b [PMID: 31465220] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pKd 4
⤷ pKd 7.8 (Kd 1.4x10-8 M) [4]
wortmannin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.0 pKd 7
⤷ pKd 5.0 (Kd 9.2x10-6 M) [7]
sapanisertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Hs Inhibition 8.9 pKi 17
⤷ pKi 8.9 (Ki 1.4x10-9 M) [17]
compound 82 [PMID: 21332118] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pKi 8
⤷ pKi 8.7 (Ki 2x10-9 M) [8]
PQR620 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pKi 32
⤷ pKi 8.0 (Ki 1.08x10-8 M) [32]
Description: In vitro inhibition constant.
PF-04691502 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pKi 23
⤷ pKi 7.8 (Ki 1.6x10-8 M) [23]
apitolisib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pKi 38
⤷ pKi 7.8 (Ki 1.7x10-8 M) [38]
omipalisib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.5 – 6.7 pKi 20
⤷ pKi 6.5 – 6.7 (Ki 3x10-7 – 1.8x10-7 M) [20]
berzosertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition <6.0 pKi 10
⤷ pKi <6.0 (Ki >1x10-6 M) [10]
eCF309 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.1 pEC50 11
⤷ pEC50 8.1 (EC50 9x10-9 M) [11]
Description: In a cell viability assay.
ridaforolimus Small molecule or natural product Primary target of this compound Hs Inhibition 9.7 pIC50 35
⤷ pIC50 9.7 (IC50 2x10-10 M) [35]
Description: Measured as dose-dependent inhibition of phosphorylation of ribosomal protein S6, a signaling protein downstream of mTOR
torin 1 Small molecule or natural product Primary target of this compound Hs Inhibition 9.5 pIC50 25
⤷ pIC50 9.5 (IC50 2.9x10-10 M) [25]
Description: Assayed using mTORC1 complex
AZD8055 Small molecule or natural product Primary target of this compound Hs Inhibition 9.1 pIC50 31
⤷ pIC50 9.1 (IC50 8x10-10 M) [31]
sapanisertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Hs Inhibition 9.0 pIC50 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
gedatolisib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.8 pIC50 40
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [40]
everolimus Small molecule or natural product Approved drug Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 37
⤷ pIC50 8.7 (IC50 2x10-9 M) [37]
vistusertib Small molecule or natural product Primary target of this compound Hs Inhibition 8.6 pIC50 31
⤷ pIC50 8.6 (IC50 2.8x10-9 M) [31]
Description: Assay using FLAG-tagged human mTOR(1362-2549)
torin 2 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.6 pIC50 26
⤷ pIC50 8.6 (IC50 2.81x10-9 M) [26]
panulisib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 18
⤷ pIC50 8.4 (IC50 4.4x10-9 M) [18]
Description: Using a radiometric protein kinase (33PanQinase activity) assay.
WYE-354 Small molecule or natural product Primary target of this compound Hs Inhibition 8.3 pIC50 43
⤷ pIC50 8.3 (IC50 5x10-9 M) [43]
Description: DELFIA assay measuring His6-S6K1 T389 phosphorylation.
compound 7 [PMID: 31955578] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 3
⤷ pIC50 8.3 (IC50 5.6x10-9 M) [3]
Description: IC50 for inhibition of mTOR-induced phosphorylation of S6 protein in a cellular assay.
dactolisib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.2 pIC50 27
⤷ pIC50 8.2 (IC50 6x10-9 M) [27]
Description: Measured as inhibition of downstream mTOR activated p70S6K
PP-242 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 1
⤷ pIC50 8.1 (IC50 8x10-9 M) [1]
CZ415 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 6
⤷ pIC50 8.1 (IC50 8.51x10-9 M) [6]
Description: Assessed in a competition binding assay using a mixed inhibitor lipid kinase matrix.
XL388 Small molecule or natural product Primary target of this compound Hs Inhibition 8.0 pIC50 39
⤷ pIC50 8.0 (IC50 9.9x10-9 M) [39]
PP121 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 1
⤷ pIC50 8.0 (IC50 1x10-8 M) [1]
onatasertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.0 pIC50 28
⤷ pIC50 8.0 (IC50 1x10-8 M) [28]
KU-0063794 Small molecule or natural product Primary target of this compound Hs Inhibition 8.0 pIC50 13
⤷ pIC50 8.0 (IC50 1x10-8 M) [13]
Description: Inhibition of immunoprecipitated mTORC1 (S6K1 as substrate) and mTORC2 (Akt as substrate).
eCF309 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 11
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [11]
Description: In a biochemical assys using recombinant wild type enzyme.
compound 15a [PMID: 32069401] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 44
⤷ pIC50 7.7 (IC50 2.1x10-8 M) [44]
PI-103 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 33
⤷ pIC50 7.5 (IC50 3x10-8 M) [33]
VS-5584 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.4 pIC50 15
⤷ pIC50 7.4 (IC50 3.7x10-8 M) [15]
DS-7423 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 19
⤷ pIC50 7.4 (IC50 3.94x10-8 M) [19]
copanlisib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 24
⤷ pIC50 7.3 (IC50 4.5x10-8 M) [24]
compound 11j [PMID: 23021994] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 14
⤷ pIC50 7.3 (IC50 5x10-8 M) [14]
paxalisib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 16
⤷ pIC50 7.2 (IC50 7x10-8 M) [16]
samotolisib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 6.8 pIC50 2
⤷ pIC50 6.8 (IC50 1.65x10-7 M) [2]
zandelisib Small molecule or natural product Click here for species-specific activity table Hs Inhibition <6.3 pIC50 5
⤷ pIC50 <6.3 (IC50 >5x10-7 M) [5]
temsirolimus Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Inhibition 5.8 pIC50 21
⤷ pIC50 5.8 (IC50 1.76x10-6 M) [21]
izorlisib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.8 pIC50 30
⤷ pIC50 5.8 (IC50 1.6x10-6 M) [30]
STK16-IN-1 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.3 pIC50 22
⤷ pIC50 5.3 (IC50 5.56x10-6 M) [22]
Description: In an in vitro enzymatic assay.
serabelisib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >5.0 pIC50 34
⤷ pIC50 >5.0 (IC50 <1x10-5 M) [34]
RapaLink-1 Small molecule or natural product Hs Inhibition - - 36
⤷ [36]
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: 9,42
Key to terms and symbols Click column headers to sort
Target used in screen: MTOR
Ligand Sp. Type Action Value Parameter
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
PI-103 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
pictilisib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
TG-100-115 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 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: 12...
Key to terms and symbols Click column headers to sort
Target used in screen: mTOR-FKBP12/nd
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
sirolimus Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition -17.0 4.0
PI-103 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition -12.0 7.0
AG 9 Small molecule or natural product Hs Inhibitor Inhibition 70.0 101.0
Akt inhibitor X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 70.0 98.0
CGP74514A Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 70.0 109.0
AG 1295 Small molecule or natural product Hs Inhibitor Inhibition 70.0 83.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 72.0 99.0
CGP53353 Small molecule or natural product Hs Inhibitor Inhibition 73.0 85.0
MEK inhibitor I Small molecule or natural product Hs Inhibitor Inhibition 74.0 95.0
PDGF RTK inhibitor Small molecule or natural product Hs Inhibitor Inhibition 75.0 111.0
Target used in screen: mTOR/nd
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
LY 294002 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 24.0 27.0
PI 3-Kg inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 46.0 51.0
PI-103 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 49.0 35.0
PKR inhibitor, negative control Small molecule or natural product Hs Inhibitor Inhibition 51.0 64.0
sirolimus Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 57.0 51.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 73.0 73.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 75.0 71.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 76.0 76.0
AG 1024 Small molecule or natural product Hs Inhibitor Inhibition 77.0 86.0
diacylglycerol kinase inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 78.0 85.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Inflammation
Immuno Process:  Immune system development
Immuno Process:  B cell (activation)
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Nonsense Human M2327I Activating mutation in the kinase domain of mTOR, which could theoretically confer a growth advantage in transformed cancer cells. 36
Clinically-Relevant Mutations and Pathophysiology Comments
Hyperactivation of mTOR kinase by single amino acid mutations such as M2327I (which has been identified in drug-naive patients) can reduce sensitivity to ATP-competitive mTOR inhibitors in vitro [36].

References

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3. Bonazzi S, Goold CP, Gray A, Thomsen NM, Nunez J, Karki RG, Gorde A, Biag JD, Malik HA, Sun Y et al.. (2020) Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders. J Med Chem, 63 (3): 1068-1083. [PMID:31955578]

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5. Brown SD, Matthews DJ. (2012) (alpha- substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5 -triazinyl benzimidazoles, pharmaceutical compositions containing them, and these compounds for use in treating proliferative diseases. Patent number: WO2012135160A1. Assignee: Pathway Therapeutics Inc.. Priority date: 28/03/2011. Publication date: 04/10/2012.

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12. 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]

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16. Heffron TP, Ndubaku CO, Salphati L, Alicke B, Cheong J, Drobnick J, Edgar K, Gould SE, Lee LB, Lesnick JD et al.. (2016) Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med Chem Lett, 7 (4): 351-6. [PMID:27096040]

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20. Knight SD, Adams ND, Burgess JL, Chaudhari AM, Darcy MG, Donatelli CA, Luengo JI, Newlander KA, Parrish CA, Ridgers LH et al.. (2010) Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett, 1 (1): 39-43. [PMID:24900173]

21. Kong F, Zhu T, Yu K, Pagano TG, Desai P, Radebaugh G, Fawzi M. (2011) Isolation and structure of homotemsirolimuses A, B, and C. J Nat Prod, 74 (4): 547-53. [PMID:21438579]

22. Liu F, Wang J, Yang X, Li B, Wu H, Qi S, Chen C, Liu X, Yu K, Wang W et al.. (2016) Discovery of a Highly Selective STK16 Kinase Inhibitor. ACS Chem Biol, 11 (6): 1537-43. [PMID:27082499]

23. Liu KK, Zhu J, Smith GL, Yin MJ, Bailey S, Chen JH, Hu Q, Huang Q, Li C, Li QJ et al.. (2011) Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity. ACS Med Chem Lett, 2 (11): 809-13. [PMID:24900269]

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25. Liu Q, Chang JW, Wang J, Kang SA, Thoreen CC, Markhard A, Hur W, Zhang J, Sim T, Sabatini DM et al.. (2010) Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J Med Chem, 53 (19): 7146-55. [PMID:20860370]

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How to cite this page

FRAP subfamily: mechanistic target of rapamycin kinase. Last modified on 19/04/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2109.