Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 15, Pages 4967-4974Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.06.033
Keywords
mTOR; Kinase inhibitor; Oncology; Imidazopyridine; Imidazopyridazine
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mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series. (c) 2012 Published by Elsevier Ltd.
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