title: Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin.
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.
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Knight
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Adams
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Joelle L
authors.initials: JL
authors.lastname: Burgess
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Amita M
authors.initials: AM
authors.lastname: Chaudhari
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Darcy
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Donatelli
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Newlander
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Parrish
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Lance H
authors.initials: LH
authors.lastname: Ridgers
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Sarpong
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Schmidt
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Van Aller
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Carson
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Diamond
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Elkins
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gardiner
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Eric
authors.initials: E
authors.lastname: Garver
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Gilbert
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Gontarek
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Kershner
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Raha
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Sherk
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Chiu-Mei
authors.initials: CM
authors.lastname: Sung
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wegrzyn
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Auger
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
keywords: GSK2126458; PI3K/AKT pathway; mammalian target of rapamycin; phosphoinositide 3-kinase α