PMID- 26102506
OWN - NLM
STAT- MEDLINE
DCOM- 20151012
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 58
IP  - 14
DP  - 2015 Jul 23
TI  - Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin 
      (mTOR) Kinase Inhibitors and the Discovery of CC-115.
PG  - 5599-608
LID - 10.1021/acs.jmedchem.5b00627 [doi]
AB  - We report here the synthesis and structure-activity relationship (SAR) of a novel 
      series of triazole containing mammalian target of rapamycin (mTOR) kinase 
      inhibitors. SAR studies examining the potency, selectivity, and PK parameters for 
      a series of triazole containing 4,6- or 
      1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the 
      identification of triazole containing mTOR kinase inhibitors with improved PK 
      properties. Potent compounds from this series were found to block both 
      mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in 
      vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy 
      in tumor xenograft models. This work resulted in the selection of CC-115 for 
      clinical development.
FAU - Mortensen, Deborah S
AU  - Mortensen DS
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Perrin-Ninkovic, Sophie M
AU  - Perrin-Ninkovic SM
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Shevlin, Graziella
AU  - Shevlin G
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Elsner, Jan
AU  - Elsner J
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Zhao, Jingjing
AU  - Zhao J
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Whitefield, Brandon
AU  - Whitefield B
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Tehrani, Lida
AU  - Tehrani L
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Sapienza, John
AU  - Sapienza J
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Riggs, Jennifer R
AU  - Riggs JR
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Parnes, Jason S
AU  - Parnes JS
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Papa, Patrick
AU  - Papa P
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Packard, Garrick
AU  - Packard G
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Lee, Branden G S
AU  - Lee BG
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Harris, Roy
AU  - Harris R
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Correa, Matthew
AU  - Correa M
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Bahmanyar, Sogole
AU  - Bahmanyar S
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Richardson, Samantha J
AU  - Richardson SJ
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Peng, Sophie X
AU  - Peng SX
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Leisten, Jim
AU  - Leisten J
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Khambatta, Godrej
AU  - Khambatta G
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Hickman, Matt
AU  - Hickman M
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Gamez, James C
AU  - Gamez JC
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Bisonette, Rene R
AU  - Bisonette RR
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Apuy, Julius
AU  - Apuy J
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Cathers, Brian E
AU  - Cathers BE
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Canan, Stacie S
AU  - Canan SS
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Moghaddam, Mehran F
AU  - Moghaddam MF
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Raymon, Heather K
AU  - Raymon HK
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Worland, Peter
AU  - Worland P
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Narla, Rama Krishna
AU  - Narla RK
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Fultz, Kimberly E
AU  - Fultz KE
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
FAU - Sankar, Sabita
AU  - Sankar S
AD  - Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 
      92121, United States.
LA  - eng
PT  - Journal Article
DEP - 20150708
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazines)
RN  - 0 (Triazoles)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - FII75TFH5L 
      (1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - *Drug Design
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Protein Conformation
MH  - Protein Kinase Inhibitors/*chemistry/metabolism/pharmacokinetics/*pharmacology
MH  - Pyrazines/*chemistry/metabolism/pharmacokinetics/*pharmacology
MH  - Rats
MH  - Signal Transduction/drug effects
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/chemistry/metabolism
MH  - Triazoles/*chemistry/metabolism/pharmacokinetics/*pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2015/06/24 06:00
MHDA- 2015/10/13 06:00
CRDT- 2015/06/24 06:00
PHST- 2015/06/24 06:00 [entrez]
PHST- 2015/06/24 06:00 [pubmed]
PHST- 2015/10/13 06:00 [medline]
AID - 10.1021/acs.jmedchem.5b00627 [doi]
PST - ppublish
SO  - J Med Chem. 2015 Jul 23;58(14):5599-608. doi: 10.1021/acs.jmedchem.5b00627. Epub 
      2015 Jul 8.