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. 2010 Jan 19;1(1):39-43.
doi: 10.1021/ml900028r. eCollection 2010 Apr 8.

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

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

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

Steven D Knight et al. ACS Med Chem Lett. .

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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Figures

Figure 1
Figure 1
GlaxoSmithKline PI3K clinical compounds.
Scheme 1
Scheme 1. Synthesis of TZD Replacement Analogs
Conditions: (a) 2 M HCl, ether; then NaI, EtCN, reflux. (b) 4-Pyridylboronic acid, Pd(PPh3)4, 2 M aqueous K2CO3, dioxane, 100 °C. (c) Pinacolato(diboron), PdCl2(dppf)-CH2Cl2, KOAc, dioxane, 100 °C; then ArBr, 2 M aqueous Na2CO3, 110 °C.
Figure 2
Figure 2
X-ray cocrystal structure of p110γ with 6d. The protein is shown in the solid ribbon. Selected residues are shown in gray. Figures 2 and 3 were prepared using PyMOL.
Figure 3
Figure 3
X-ray cocrystal structure of p110γ with GSK2126458 (1).
Figure 4
Figure 4
PD effect of 1 in BT474 human tumor xenografts following a single 300 μg kg−1 oral dose. The ratio of pAKT/total AKT was measured and compared to control. [Blood], concentration of drug in the blood in ng mL−1; NQ, not quantifiable.
Figure 5
Figure 5
Tumor growth efficacy of 1 in BT474 human tumor xenografts as measured by median tumor volume (cu mm). Mice were dosed once daily for 5 days/week (M−F) for 3 weeks (days 17−21, 24−28, and 31−35). Error bars denote the standard error of the mean (SEM).
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