Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTCJG29)

• DTT Name: Serine/threonine-protein kinase mTOR (mTOR)
• Synonyms: Target of rapamycin; TOR kinase; Rapamycin target protein 1; Rapamycin target protein; Rapamycin and FKBP12 target 1; RAPT1; RAFT1; Mechanistic target of rapamycin; Mammalian target of rapamycin; FRAP2; FRAP1; FRAP; FKBP12-rapamycin complex-associated protein; FKBP-rapamycin associated protein; FK506-binding protein 12-rapamycin complex-associated protein 1
• Gene Name: MTOR
• DTT Type: Successful target; [1]
• Related Disease:
  Arteries/arterioles disorder [ICD-11: BD52]
  Chronic myelomonocytic leukaemia [ICD-11: 2A40]
  Multiple myeloma [ICD-11: 2A83]
  Renal cell carcinoma [ICD-11: 2C90]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
  Transplant rejection [ICD-11: NE84]
• BioChemical Class: Kinase
• UniProt ID: MTOR_HUMAN
• TTD ID: T75243
• EC Number: EC 2.7.11.1
• Sequence:
  MLGTGPAAATTAATTSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTMELREMSQEES
  TRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGNATRIGRFANYLRNLLPSNDP
  VVMEMASKAIGRLAMAGDTFTAEYVEFEVKRALEWLGADRNEGRRHAAVLVLRELAISVP
  TFFFQQVQPFFDNIFVAVWDPKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEE
  AEKGFDETLAKEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYC
  KDLMGFGTKPRHITPFTSFQAVQPQQSNALVGLLGYSSHQGLMGFGTSPSPAKSTLVESR
  CCRDLMEEKFDQVCQWVLKCRNSKNSLIQMTILNLLPRLAAFRPSAFTDTQYLQDTMNHV
  LSCVKKEKERTAAFQALGLLSVAVRSEFKVYLPRVLDIIRAALPPKDFAHKRQKAMQVDA
  TVFTCISMLARAMGPGIQQDIKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLL
  KMLSLVLMHKPLRHPGMPKGLAHQLASPGLTTLPEASDVGSITLALRTLGSFEFEGHSLT
  QFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQVVADVLSKLL
  VVGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVALNDQVFEIRELAICTVGRLSS
  MNPAFVMPFLRKMLIQILTELEHSGIGRIKEQSARMLGHLVSNAPRLIRPYMEPILKALI
  LKLKDPDPDPNPGVINNVLATIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVA
  LWTLGQLVASTGYVVEPYRKYPTLLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHK
  VNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAVSMVALMRIFR
  DQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNVIRVCDGAIREFLFQQLGMLV
  SFVKSHIRPYMDEIVTLMREFWVMNTSIQSTIILLIEQIVVALGGEFKLYLPQLIPHMLR
  VFMHDNSPGRIVSIKLLAAIQLFGANLDDYLHLLLPPIVKLFDAPEAPLPSRKAALETVD
  RLTESLDFTDYASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLV
  RHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSGQGDALASGPVETGPMKKLHV
  STINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSLRSCWALAQAYNPMARDLFNA
  AFVSCWSELNEDQQDELIRSIELALTSQDIAEVTQTLLNLAEFMEHSDKGPLPLRDDNGI
  VLLGERAAKCRAYAKALHYKELEFQKGPTPAILESLISINNKLQQPEAAAGVLEYAMKHF
  GELEIQATWYEKLHEWEDALVAYDKKMDTNKDDPELMLGRMRCLEALGEWGQLHQQCCEK
  WTLVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVLALHQDLFSLA
  QQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELEEVIQYKLVPERREIIRQIWW
  ERLQGCQRIVEDWQKILMVRSLVVSPHEDMRTWLKYASLCGKSGRLALAHKTLVLLLGVD
  PSRQLDHPLPTVHPQVTYAYMKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHK
  QELHKLMARCFLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEA
  VLHYKHQNQARDEKKKLRHASGANITNATTAATTAATATTTASTEGSNSESEAESTENSP
  TPSPLQKKVTEDLSKTLLMYTVPAVQGFFRSISLSRGNNLQDTLRVLTLWFDYGHWPDVN
  EALVEGVKAIQIDTWLQVIPQLIARIDTPRPLVGRLIHQLLTDIGRYHPQALIYPLTVAS
  KSTTTARHNAANKILKNMCEHSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFG
  ERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQA
  WDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPIIRIQSIAPSL
  QVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQLFGLVNTLLANDPTSLRKNL
  SIQRYAVIPLSTNSGLIGWVPHCDTLHALIRDYREKKKILLNIEHRIMLRMAPDYDHLTL
  MQKVEVFEHAVNNTAGDDLAKLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRH
  PSNLMLDRLSGKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRITC
  HTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDTNTKGNKRSRTRTDSYSAGQSVEILDG
  VELGEPAHKKTGTTVPESIHSFIGDGLVKPEALNKKAIQIINRVRDKLTGRDFSHDDTLD
  VPTQVELLIKQATSHENLCQCYIGWCPFW
• Function: MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms. Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks. Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
• KEGG Pathway:
  ErbB signaling pathway (hsa04012)
  HIF-1 signaling pathway (hsa04066)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Insulin signaling pathway (hsa04910)
  Thyroid hormone signaling pathway (hsa04919)
  Adipocytokine signaling pathway (hsa04920)
  Type II diabetes mellitus (hsa04930)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Acute myeloid leukemia (hsa05221)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  mTORC1-mediated signalling (R-HSA-166208)
  HSF1-dependent transactivation (R-HSA-3371571)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DTT

6 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Everolimus	DM8X2EH	Renal cell carcinoma	2C90	Approved	[2]
Novolimus	DM6ZPLQ	Artery stenosis	BD52	Approved	[3]
PF-04449913	DMSB068	Chronic myelomonocytic leukaemia	2A40	Approved	[4]
Sirolimus	DMGW1ID	Multiple myeloma	2A83	Approved	[5]
Temsirolimus	DMS104F	Renal cell carcinoma	2C90	Approved	[1], [6]
Zotarolimus	DMRMCXW	Solid tumour/cancer	2A00-2F9Z	Approved	[7]

25 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ridaforolimus	DMLHEU7	Sarcoma	2A60-2C35	Phase 3	[8], [9]
ABI-009	DMQ6KZM	Malignant perivascular epithelioid cell tumour	2B5Y	Phase 2	[10]
Azd2014	DMOEARH	Solid tumour/cancer	2A00-2F9Z	Phase 2	[11]
BEZ235	DMKBRDL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[12]
GDC-0980/RG7422	DMF3MV1	Non-hodgkin lymphoma	2B33.5	Phase 2	[3], [13]
INK128	DMGO7QT	Breast cancer	2C60-2C65	Phase 2	[14]
LY3023414	DMD9KYF	Prostate cancer	2C82.0	Phase 2	[15]
MM-141	DM2RJ4D	Pancreatic cancer	2C10	Phase 2	[10]
OSI-027	DMJX3O8	Renal cell carcinoma	2C90	Phase 2	[16]
PF-04691502	DMS610L	Endometrial cancer	2C76	Phase 2	[17]
PF-05212384	DMBL3VD	Solid tumour/cancer	2A00-2F9Z	Phase 2	[18]
PQR309	DMMCYZ8	Squamous head and neck cell carcinom	2D60.0	Phase 2	[3]
Salirasib	DMRSU4X	Lung cancer	2C25.0	Phase 2	[3]
SAR245409	DMQM7IL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[3], [19]
SF1126	DML10K3	Head and neck cancer	2D42	Phase 2	[10]
BGT226	DMXKDUL	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[20]
CC-223	DMMQYL9	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[21]
ME-344	DM6JN19	Breast cancer	2C60-2C65	Phase 1/2	[22]
BI 860585	DMMQ12N	Solid tumour/cancer	2A00-2F9Z	Phase 1	[23]
DS-3078	DMG7I5J	Lymphoma	2A80-2A86	Phase 1	[24]
DS-7423	DMCFJM3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[25]
GDC-0349	DM3Z2JB	Non-hodgkin lymphoma	2B33.5	Phase 1	[26]
LAM-001	DM7JNHU	Lymphangioleiomyomatosis	CB07	Phase 1	[27]
PWT-33597	DMJY15D	Solid tumour/cancer	2A00-2F9Z	Phase 1	[28]
VS-5584	DMMO3G5	Malignant mesothelioma	2C26.0	Phase 1	[3], [29]

5 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID25726713-Compound-47	DMXE5KM	N. A.	N. A.	Patented	[30]
PMID25726713-Compound-48	DMSIOUA	N. A.	N. A.	Patented	[30]
PMID25726713-Compound-49	DM2CT4G	N. A.	N. A.	Patented	[30]
PMID25726713-Compound-50	DM3BDFV	N. A.	N. A.	Patented	[30]
PMID25726713-Compound-51	DMF0OW4	N. A.	N. A.	Patented	[30]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD8055	DM7L8SG	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1/2	[31]
TAFA-93	DMI52NT	Transplant rejection	NE84	Discontinued in Phase 1	[32]
SCR-44001	DMFZNUA	Solid tumour/cancer	2A00-2F9Z	Terminated	[33]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(4-(6-morpholino-9H-purin-2-yl)phenyl)methanol	DMUOFW8	Discovery agent	N.A.	Investigative	[34]
2-(2-Methyl-morpholin-4-yl)-benzo[h]chromen-4-one	DMAHZR9	Discovery agent	N.A.	Investigative	[35]
2-(6-morpholino-9H-purin-2-yl)phenol	DMZDNHQ	Discovery agent	N.A.	Investigative	[34]
2-chloro-N-(6-cyanopyridin-3-yl)propanamide	DMBKVM4	Discovery agent	N.A.	Investigative	[36]
2-Morpholin-4-yl-pyrimido[2,1-a]isoquinolin-4-one	DM79ZOV	Discovery agent	N.A.	Investigative	[35]
3-(6-morpholino-9H-purin-2-yl)phenol	DMS2OY9	Discovery agent	N.A.	Investigative	[34]
4-(2-(1H-indol-6-yl)-9H-purin-6-yl)morpholine	DMTJGBL	Discovery agent	N.A.	Investigative	[34]
4-(2-(thiophen-2-yl)-9H-purin-6-yl)morpholine	DMWN1CM	Discovery agent	N.A.	Investigative	[34]
4-(2-(thiophen-3-yl)-9H-purin-6-yl)morpholine	DMAO6X9	Discovery agent	N.A.	Investigative	[34]
4-(6-morpholino-9H-purin-2-yl)phenol	DM1Z3N6	Discovery agent	N.A.	Investigative	[34]
AP-21967	DMCNG74	Discovery agent	N.A.	Investigative	[37]
AR-mTOR-26	DM24MKI	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
C-16-(S)-3-methylindolerapamycin	DMZXE6O	Discovery agent	N.A.	Investigative	[37]
CU-906	DMY1WEM	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
EC-0565	DMIC372	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
EC-0845	DMK6E10	Inflammation	1A00-CA43.1	Investigative	[3]
EM-101	DMQ63J2	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
Ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxylate	DM3FH02	Discovery agent	N.A.	Investigative	[35]
HM-5016699	DMKHVUE	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
OXA-01	DMCFM2E	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
P-2281	DMZI8QW	Ulcerative colitis	DD71	Investigative	[3]
P-6915	DMJDI7O	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
PF-03772304	DMJ0936	Solid tumour/cancer	2A00-2F9Z	Investigative	[38]
PF-05094037	DMZAE97	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
PP-242	DM2348V	Discovery agent	N.A.	Investigative	[39]
PP121	DMU8KTO	Discovery agent	N.A.	Investigative	[39]
Rapamycin complexed with immunophilin FKBP12	DMLBP3F	Discovery agent	N.A.	Investigative	[40]
SB-2280	DMIBS95	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
SX-MTR1	DMJGZ79	Bladder cancer	2C94	Investigative	[3]
torin 1	DMZD0NA	Discovery agent	N.A.	Investigative	[41]
Torin2	DMC6U93	T-cell leukaemia	2A90	Investigative	[42]
X-387	DMZ0TDL	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Renal cancer	2C82	Kidney	2.16E-05	-0.44	-2.3
Sarcoma	2C82	Muscle tissue	6.68E-99	-0.33	-1.42
Uterine cancer	2C82	Endometrium tissue	1.14E-06	0.12	0.55
Multiple myeloma	2C82	Bone marrow	1.21E-03	-0.24	-1.75
Bladder cancer	2C82	Bladder tissue	1.72E-04	0.42	3.19

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