Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).
We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
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
Grosu
George
G
Bursavich
Matthew G
MG
Bard
Joel
J
Brooijmans
Natasja
N
Toral-Barza
Lourdes
L
Hollander
Irwin
I
Mansour
Tarek S
TS
Ayral-Kaloustian
Semiramis
S
Yu
Ker
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D001572:Benzofurans; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse