Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.
The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
Venkatesan
Aranapakam M
AM
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
Dehnhardt
Christoph M
CM
Delos Santos
Efren
E
Chen
Zecheng
Z
Dos Santos
Osvaldo
O
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
James
J
Abraham
Robert T
RT
Chaudhary
Inder
I
Mansour
Tarek S
TS
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000255:Adenosine Triphosphate; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C549060:gedatolisib; C546842:MTOR protein, human; C546843:mTOR protein, mouse