Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors.
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Venkatesan
Aranapakam M
AM
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, United States. venkata@wyeth.com
Dehnhardt
Christoph M
CM
Chen
Zecheng
Z
Santos
Efren Delos
ED
Dos Santos
Osvaldo
O
Bursavich
Matthew
M
Gilbert
Adam M
AM
Ellingboe
John W
JW
Ayral-Kaloustian
Semiramis
S
Khafizova
Gulnaz
G
Brooijmans
Natasja
N
Mallon
Robert
R
Hollander
Irwin
I
Feldberg
Larry
L
Lucas
Judy
J
Yu
Ker
K
Gibbons
Jay
J
Abraham
Robert
R
Mansour
Tarek S
TS
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000255:Adenosine Triphosphate; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human