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

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

ACS medicinal chemistry letters (2010-04-08)
Steven D Knight, Nicholas D Adams, Joelle L Burgess, Amita M Chaudhari, Michael G Darcy, Carla A Donatelli, Juan I Luengo, Ken A Newlander, Cynthia A Parrish, Lance H Ridgers, Martha A Sarpong, Stanley J Schmidt, Glenn S Van Aller, Jeffrey D Carson, Melody A Diamond, Patricia A Elkins, Christine M Gardiner, Eric Garver, Seth A Gilbert, Richard R Gontarek, Jeffrey R Jackson, Kevin L Kershner, Lusong Luo, Kaushik Raha, Christian S Sherk, Chiu-Mei Sung, David Sutton, Peter J Tummino, Ronald J Wegrzyn, Kurt R Auger, Dashyant Dhanak
PMID24900173
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.