2. Academic Validation
  3. 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 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

Affiliation

  • 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.

Figures
Products