2. Academic Validation
  3. Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer

Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer

  • J Med Chem. 2010 Feb 11;53(3):1086-97. doi: 10.1021/jm901284w.
Daniel P Sutherlin 1,  Deepak Sampath,  Megan Berry,  Georgette Castanedo,  Zhigang Chang,  Irina Chuckowree,  Jenna Dotson,  Adrian Folkes,  Lori Friedman,  Richard Goldsmith,  Tim Heffron,  Leslie Lee,  John Lesnick,  Cristina Lewis,  Simon Mathieu,  Jim Nonomiya,  Alan Olivero,  Jodie Pang,  Wei Wei Prior,  Laurent Salphati,  Steve Sideris,  Qingping Tian,  Vickie Tsui,  Nan Chi Wan,  Shumei Wang,  Christian Wiesmann,  Susan Wong,  Bing-Yan Zhu
Affiliations

Affiliation

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. sutherlin.dan@gene.com
PMID: 20050669 DOI: 10.1021/jm901284w
Abstract

The PI3K/Akt/mTOR pathway has been shown to play an important role in Cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.

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