PMID- 22832322
OWN - NLM
STAT- MEDLINE
DCOM- 20130107
LR  - 20211203
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 22
IP  - 17
DP  - 2012 Sep 1
TI  - Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based 
      on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.
PG  - 5714-20
LID - 10.1016/j.bmcl.2012.06.078 [doi]
AB  - Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the 
      deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A 
      series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and 
      evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, 
      pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are 
      described. The most promising compound from this investigation (compound 3j) was 
      found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity 
      over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG 
      cellular assay measuring phosphorylation of Akt, compound 3j displayed low double 
      digit nanomolar IC(50) and exhibited good oral bioavailability in rats 
      (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the 
      phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma 
      EC(50)=193 nM (91 ng/mL).
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Wurz, Ryan P
AU  - Wurz RP
AD  - Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, 
      Thousand Oaks, CA 91320, USA. rwurz@amgen.com
FAU - Liu, Longbin
AU  - Liu L
FAU - Yang, Kevin
AU  - Yang K
FAU - Nishimura, Nobuko
AU  - Nishimura N
FAU - Bo, Yunxin
AU  - Bo Y
FAU - Pettus, Liping H
AU  - Pettus LH
FAU - Caenepeel, Sean
AU  - Caenepeel S
FAU - Freeman, Daniel J
AU  - Freeman DJ
FAU - McCarter, John D
AU  - McCarter JD
FAU - Mullady, Erin L
AU  - Mullady EL
FAU - Miguel, Tisha San
AU  - Miguel TS
FAU - Wang, Ling
AU  - Wang L
FAU - Zhang, Nancy
AU  - Zhang N
FAU - Andrews, Kristin L
AU  - Andrews KL
FAU - Whittington, Douglas A
AU  - Whittington DA
FAU - Jiang, Jian
AU  - Jiang J
FAU - Subramanian, Raju
AU  - Subramanian R
FAU - Hughes, Paul E
AU  - Hughes PE
FAU - Norman, Mark H
AU  - Norman MH
LA  - eng
PT  - Journal Article
DEP - 20120703
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Sulfonamides)
RN  - 0 (Triazines)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/chemistry/pharmacokinetics/pharmacology/therapeutic use
MH  - Binding Sites
MH  - Cell Line, Tumor
MH  - Crystallography, X-Ray
MH  - Female
MH  - Humans
MH  - Mice
MH  - Molecular Docking Simulation
MH  - Neoplasms/*drug therapy/enzymology/metabolism
MH  - Phosphatidylinositol 3-Kinases/chemistry/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/*chemistry/pharmacokinetics/*pharmacology/therapeutic 
      use
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Signal Transduction/drug effects
MH  - Structure-Activity Relationship
MH  - Sulfonamides/*chemistry/pharmacokinetics/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Triazines/chemistry/pharmacokinetics/pharmacology/therapeutic use
EDAT- 2012/07/27 06:00
MHDA- 2013/01/08 06:00
CRDT- 2012/07/27 06:00
PHST- 2012/05/07 00:00 [received]
PHST- 2012/06/21 00:00 [revised]
PHST- 2012/06/25 00:00 [accepted]
PHST- 2012/07/27 06:00 [entrez]
PHST- 2012/07/27 06:00 [pubmed]
PHST- 2013/01/08 06:00 [medline]
AID - S0960-894X(12)00838-4 [pii]
AID - 10.1016/j.bmcl.2012.06.078 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2012 Sep 1;22(17):5714-20. doi: 10.1016/j.bmcl.2012.06.078. 
      Epub 2012 Jul 3.