PMID- 34191518
OWN - NLM
STAT- MEDLINE
DCOM- 20220208
LR  - 20220208
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 65
IP  - 2
DP  - 2022 Jan 27
TI  - In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically 
      Inhibit the Kinase Activity of mTORC1.
PG  - 1329-1341
LID - 10.1021/acs.jmedchem.1c00536 [doi]
AB  - Cancer-specific metabolic alterations hyperactivate the kinase activity of the 
      mammalian/mechanistic target of rapamycin (mTOR) for overcoming stressful 
      environments. Rapalogs, which allosterically inhibit mTOR complex 1 (mTORC1), 
      have been approved as anticancer agents. However, the immunosuppressive side 
      effect of these compounds results in the promotion of tumor metastasis, thereby 
      limiting their therapeutic efficacy. We first report a nonrapalog inhibitor, 
      WRX606, identified by a hybrid strategy of in silico and in cell selections. Our 
      studies showed that WRX606 formed a ternary complex with FK506-binding protein-12 
      (FKBP12) and FKBP-rapamycin-binding (FRB) domain of mTOR, resulting in the 
      allosteric inhibition of mTORC1. WRX606 inhibited the phosphorylation of not only 
      the ribosomal protein S6 kinase 1 (S6K1) but also eIF4E-binding protein-1 
      (4E-BP1). Hence, WRX606 efficiently suppressed tumor growth in mice without 
      promotion of metastasis. These results suggest that WRX606 is a potent lead 
      compound for developing anticancer drugs discovered by in silico and in cell 
      methods.
FAU - Shams, Raef
AU  - Shams R
AD  - Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter 
      Science, RIKEN, Wako, Saitama 351-0198, Japan.
AD  - Department of Life Science, Graduate School of Science and Engineering, Saitama 
      University, Saitama City, Saitama 338-8570, Japan.
FAU - Matsukawa, Akihiro
AU  - Matsukawa A
AD  - Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 
      University, 2-5-1, Shikata, Kita-ku, 700-8558 Okayama, Japan.
FAU - Ochi, Yukari
AU  - Ochi Y
AD  - Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 
      University, 2-5-1, Shikata, Kita-ku, 700-8558 Okayama, Japan.
FAU - Ito, Yoshihiro
AU  - Ito Y
AUID- ORCID: 0000-0002-1154-253X
AD  - Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter 
      Science, RIKEN, Wako, Saitama 351-0198, Japan.
AD  - Nano Medical Engineering Laboratory, RIKEN Cluster for Pioneering Research, 
      RIKEN, Wako, Saitama 351-0198, Japan.
FAU - Miyatake, Hideyuki
AU  - Miyatake H
AUID- ORCID: 0000-0001-8872-9784
AD  - Department of Life Science, Graduate School of Science and Engineering, Saitama 
      University, Saitama City, Saitama 338-8570, Japan.
AD  - Nano Medical Engineering Laboratory, RIKEN Cluster for Pioneering Research, 
      RIKEN, Wako, Saitama 351-0198, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210630
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Ligands)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Allosteric Regulation
MH  - Animals
MH  - Apoptosis
MH  - Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - Cell Cycle Proteins/genetics/*metabolism
MH  - Cell Proliferation
MH  - *Computer Simulation
MH  - Female
MH  - Humans
MH  - Ligands
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Ribosomal Protein S6 Kinases, 90-kDa/genetics/*metabolism
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
EDAT- 2021/07/01 06:00
MHDA- 2022/02/09 06:00
CRDT- 2021/06/30 17:12
PHST- 2021/07/01 06:00 [pubmed]
PHST- 2022/02/09 06:00 [medline]
PHST- 2021/06/30 17:12 [entrez]
AID - 10.1021/acs.jmedchem.1c00536 [doi]
PST - ppublish
SO  - J Med Chem. 2022 Jan 27;65(2):1329-1341. doi: 10.1021/acs.jmedchem.1c00536. Epub 
      2021 Jun 30.