4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).
A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.
Tsou
Hwei-Ru
HR
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. tsouh@wyeth.com
MacEwan
Gloria
G
Birnberg
Gary
G
Zhang
Nan
N
Brooijmans
Natasja
N
Toral-Barza
Lourdes
L
Hollander
Irwin
I
Ayral-Kaloustian
Semiramis
S
Yu
Ker
K
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D020123:Sirolimus; D040681:Structural Homology, Protein; D058570:TOR Serine-Threonine Kinases
D000255:Adenosine Triphosphate; D001572:Benzofurans; D058544:Class Ib Phosphatidylinositol 3-Kinase; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546760:PIK3CG protein, human