Phospshoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: discovery and structure-activity relationships of a series of quinoline and quinoxaline derivatives.

The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3'-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure-activity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound.

[1]  Haoran Sun,et al.  Room-temperature nucleophilic aromatic fluorination: experimental and theoretical studies. , 2006, Angewandte Chemie.

[2]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[3]  Kaushik Raha,et al.  Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. , 2010, ACS medicinal chemistry letters.

[4]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[5]  Paul Workman,et al.  Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. , 2008, Current opinion in pharmacology.

[6]  G. Bemis,et al.  Kinase inhibitors and the case for CH…O hydrogen bonds in protein–ligand binding , 2002, Proteins.

[7]  Robbie Loewith,et al.  A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling , 2006, Cell.

[8]  A. Albert.  Hydration of cn bonds in heteroaromatic substances , 1967 .

[9]  Nathan T. Ihle,et al.  Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy , 2009, Molecular Cancer Therapeutics.

[10]  I. H. Pitman,et al.  Linear free energy relations governing the covalent addition of nucleophilic reagents to a nitrogen-containing heteroaromatic molecule , 1974 .

[11]  Akira Suzuki,et al.  Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998 , 1999 .

[12]  Daniel J. Freeman,et al.  Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. , 2011, Journal of medicinal chemistry.

[13]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.