A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors.
A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2 nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays.
Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA. wendyle@gene.com
Wendy
W
Lee
Daniel F
DF
Ortwine
Philippe
P
Bergeron
Kevin
K
Lau
Lichuan
L
Lin
Shiva
S
Malek
Jim
J
Nonomiya
Zhonghua
Z
Pei
Kirk D
KD
Robarge
Stephen
S
Schmidt
Steve
S
Sideris
Joseph P
JP
Lyssikatos
D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
Mammalian target of rapamycin; Oncology; PI3K/Akt/mTOR pathway; Structure based design; mTOR kinase inhibitors