| Literature DB >> 22765895 |
Emily A Peterson1, Alessandro A Boezio, Paul S Andrews, Christiane M Boezio, Tammy L Bush, Alan C Cheng, Deborah Choquette, James R Coats, Adria E Colletti, Katrina W Copeland, Michelle DuPont, Russell Graceffa, Barbara Grubinska, Joseph L Kim, Richard T Lewis, Jingzhou Liu, Erin L Mullady, Michele H Potashman, Karina Romero, Paul L Shaffer, Mary K Stanton, John C Stellwagen, Yohannes Teffera, Shuyan Yi, Ti Cai, Daniel S La.
Abstract
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.Entities:
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Year: 2012 PMID： 22765895 DOI： 10.1016/j.bmcl.2012.06.033
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823