Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin

  • ACS Med Chem Lett. 2010 Jan 19;1(1):39-43. doi: 10.1021/ml900028r.
Steven D Knight  1 ,  Nicholas D Adams  1 ,  Joelle L Burgess  1 ,  Amita M Chaudhari  1 ,  Michael G Darcy  1 ,  Carla A Donatelli  1 ,  Juan I Luengo  1 ,  Ken A Newlander  1 ,  Cynthia A Parrish  1 ,  Lance H Ridgers  1 ,  Martha A Sarpong  1 ,  Stanley J Schmidt  1 ,  Glenn S Van Aller  1 ,  Jeffrey D Carson  1 ,  Melody A Diamond  1 ,  Patricia A Elkins  1 ,  Christine M Gardiner  1 ,  Eric Garver  1 ,  Seth A Gilbert  1 ,  Richard R Gontarek  1 ,  Jeffrey R Jackson  1 ,  Kevin L Kershner  1 ,  Lusong Luo  1 ,  Kaushik Raha  1 ,  Christian S Sherk  1 ,  Chiu-Mei Sung  1 ,  David Sutton  1 ,  Peter J Tummino  1 ,  Ronald J Wegrzyn  1 ,  Kurt R Auger  1 ,  Dashyant Dhanak  1
Affiliations
  • 1. GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
PMID: 24900173 DOI: 10.1021/ml900028r
Abstract

Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/Akt pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of Cancer.

Keywords
GSK2126458; PI3K/AKT pathway; mammalian target of rapamycin; phosphoinositide 3-kinase α.
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