PMID- 21332118
OWN - NLM
STAT- MEDLINE
DCOM- 20110617
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 54
IP  - 6
DP  - 2011 Mar 24
TI  - Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase 
      (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors.
PG  - 1789-811
LID - 10.1021/jm1014605 [doi]
AB  - Phosphoinositide 3-kinase alpha (PI3Kalpha) is a lipid kinase that plays a key regulatory 
      role in several cellular processes. The mutation or amplification of this kinase 
      in humans has been implicated in the growth of multiple tumor types. 
      Consequently, PI3Kalpha has become a target of intense research for drug discovery. 
      Our studies began with the identification of benzothiazole compound 1 from a high 
      throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 
      as an early lead, based on its in vitro cellular potency. Subsequent 
      modifications of the central pyrimidine ring dramatically improved enzyme and 
      cellular potency and led to the identification of chloropyridine 70. Further 
      arylsulfonamide SAR studies optimized in vitro clearance and led to the 
      identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule 
      exhibited potent enzyme and cell activity, low clearance, and high oral 
      bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in 
      U-87 MG, A549, and HCT116 tumor xenograft models.
FAU - D'Angelo, Noel D
AU  - D'Angelo ND
AD  - Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, California 91320-1799, United States. dangelo@amgen.com
FAU - Kim, Tae-Seong
AU  - Kim TS
FAU - Andrews, Kristin
AU  - Andrews K
FAU - Booker, Shon K
AU  - Booker SK
FAU - Caenepeel, Sean
AU  - Caenepeel S
FAU - Chen, Kui
AU  - Chen K
FAU - D'Amico, Derin
AU  - D'Amico D
FAU - Freeman, Dan
AU  - Freeman D
FAU - Jiang, Jian
AU  - Jiang J
FAU - Liu, Longbin
AU  - Liu L
FAU - McCarter, John D
AU  - McCarter JD
FAU - San Miguel, Tisha
AU  - San Miguel T
FAU - Mullady, Erin L
AU  - Mullady EL
FAU - Schrag, Michael
AU  - Schrag M
FAU - Subramanian, Raju
AU  - Subramanian R
FAU - Tang, Jin
AU  - Tang J
FAU - Wahl, Robert C
AU  - Wahl RC
FAU - Wang, Ling
AU  - Wang L
FAU - Whittington, Douglas A
AU  - Whittington DA
FAU - Wu, Tian
AU  - Wu T
FAU - Xi, Ning
AU  - Xi N
FAU - Xu, Yang
AU  - Xu Y
FAU - Yakowec, Peter
AU  - Yakowec P
FAU - Yang, Kevin
AU  - Yang K
FAU - Zalameda, Leeanne P
AU  - Zalameda LP
FAU - Zhang, Nancy
AU  - Zhang N
FAU - Hughes, Paul
AU  - Hughes P
FAU - Norman, Mark H
AU  - Norman MH
LA  - eng
PT  - Journal Article
DEP - 20110218
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzothiazoles)
RN  - 0 
      (N-(6-(6-chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo(d)thiazol-2-yl)acetamide)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Sulfonamides)
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/*chemical synthesis/chemistry/pharmacology
MH  - Benzothiazoles/*chemical synthesis/chemistry/pharmacology
MH  - Binding Sites
MH  - Biological Availability
MH  - Cell Line, Tumor
MH  - Crystallography, X-Ray
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - Humans
MH  - Liver/drug effects/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Models, Molecular
MH  - Neoplasm Transplantation
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Structure-Activity Relationship
MH  - Sulfonamides/*chemical synthesis/chemistry/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Transplantation, Heterologous
EDAT- 2011/02/22 06:00
MHDA- 2011/06/18 06:00
CRDT- 2011/02/22 06:00
PHST- 2011/02/22 06:00 [entrez]
PHST- 2011/02/22 06:00 [pubmed]
PHST- 2011/06/18 06:00 [medline]
AID - 10.1021/jm1014605 [doi]
PST - ppublish
SO  - J Med Chem. 2011 Mar 24;54(6):1789-811. doi: 10.1021/jm1014605. Epub 2011 Feb 18.