A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors |
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| Authors: | Wendy Lee Daniel F Ortwine Philippe Bergeron Kevin Lau Lichuan Lin Shiva Malek Jim Nonomiya Zhonghua Pei Kirk D Robarge Stephen Schmidt Steve Sideris Joseph P Lyssikatos |
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| Institution: | 1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. Department of Biochemical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;3. Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA |
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| Abstract: | 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 pyrrolo3,2-d]pyrimidines and pyrazolo4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo4,3-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. |
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| Keywords: | Mammalian target of rapamycin mTOR kinase inhibitors PI3K/Akt/mTOR pathway Structure based design Oncology |
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