PMID- 37175557
OWN - NLM
STAT- MEDLINE
DCOM- 20230515
LR  - 20230515
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 9
DP  - 2023 Apr 25
TI  - AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the 
      Lifespan of C. elegans.
LID - 10.3390/ijms24097850 [doi]
LID - 7850
AB  - The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets 
      for promoting health and lifespan extension. Besides rapamycin, only a few other 
      mTOR inhibitors have been developed and shown to be capable of slowing aging. We 
      used machine learning to predict novel small molecules targeting mTOR. We 
      selected one small molecule, TKA001, based on in silico predictions of a high 
      on-target probability, low toxicity, favorable physicochemical properties, and 
      preferable ADMET profile. We modeled TKA001 binding in silico by molecular 
      docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 
      signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation 
      in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that 
      TKA001 is able to slow aging in vivo.
FAU - Vidovic, Tinka
AU  - Vidovic T
AUID- ORCID: 0000-0003-0092-9365
AD  - Tinka Therapeutics, Fra Ivana Rozica 7, 21276 Vrgorac, Croatia.
FAU - Dakhovnik, Alexander
AU  - Dakhovnik A
AD  - Laboratory of Extracellular Matrix Regeneration, Institute of Translational 
      Medicine, Department of Health Sciences and Technology, ETH Zurich, CH-8603 
      Schwerzenbach, Switzerland.
FAU - Hrabovskyi, Oleksii
AU  - Hrabovskyi O
AD  - Palladin Institute of Biochemistry of the NAS of Ukraine, 02000 Kyiv, Ukraine.
FAU - MacArthur, Michael R
AU  - MacArthur MR
AD  - Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, 
      NJ 08540, USA.
FAU - Ewald, Collin Y
AU  - Ewald CY
AUID- ORCID: 0000-0003-1166-4171
AD  - Laboratory of Extracellular Matrix Regeneration, Institute of Translational 
      Medicine, Department of Health Sciences and Technology, ETH Zurich, CH-8603 
      Schwerzenbach, Switzerland.
LA  - eng
GR  - 190072/SNSF_/Swiss National Science Foundation/Switzerland
PT  - Journal Article
DEP - 20230425
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (MTOR Inhibitors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Caenorhabditis elegans Proteins)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Caenorhabditis elegans/metabolism
MH  - Longevity
MH  - MTOR Inhibitors
MH  - Molecular Docking Simulation
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Caenorhabditis elegans Proteins/metabolism
MH  - Sirolimus/pharmacology
MH  - Cell Proliferation
MH  - Artificial Intelligence
MH  - *Neoplasms/drug therapy
PMC - PMC10177929
OTO - NOTNLM
OT  - AI drug discovery
OT  - C. elegans
OT  - cancer
OT  - longevity
OT  - mTOR
OT  - rapalog
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest. T.V., M.R.M., and C.Y.E. are co-founders of Tinka 
      Therapeutics. C.Y.E. is a co-founder and shareholder of Avea Life AG, and is on 
      the Scientific Advisory Board of Maximon AG, Biotein, Longaevus Technologies 
      Ltd., and Galyan Bio, Inc.
EDAT- 2023/05/13 15:12
MHDA- 2023/05/15 11:42
PMCR- 2023/04/25
CRDT- 2023/05/13 01:27
PHST- 2023/02/09 00:00 [received]
PHST- 2023/04/21 00:00 [revised]
PHST- 2023/04/22 00:00 [accepted]
PHST- 2023/05/15 11:42 [medline]
PHST- 2023/05/13 15:12 [pubmed]
PHST- 2023/05/13 01:27 [entrez]
PHST- 2023/04/25 00:00 [pmc-release]
AID - ijms24097850 [pii]
AID - ijms-24-07850 [pii]
AID - 10.3390/ijms24097850 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Apr 25;24(9):7850. doi: 10.3390/ijms24097850.