Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies.
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
Gilbert
Adam M
AM
Medicinal Chemistry, Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. gilbera@wyeth.com
Nowak
Pawel
P
Brooijmans
Natasja
N
Bursavich
Matthew G
MG
Dehnhardt
Christoph
C
Santos
Efren Delos
ED
Feldberg
Larry R
LR
Hollander
Irwin
I
Kim
Stephen
S
Lombardi
Sabrina
S
Park
Kaapjoo
K
Venkatesan
Aranapakam M
AM
Mallon
Robert
R
D001665:Binding Sites; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D058570:TOR Serine-Threonine Kinases; C118531:pyrazolopyridine; C546842:MTOR protein, human