Synthesis and structure–activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold
| Autor: | Yunxin Bo, Tisha San Miguel, Nobuko Nishimura, Jian Jiang, Douglas A. Whittington, Paul E. Hughes, Sean Caenepeel, Mark H. Norman, John D. McCarter, Erin L. Mullady, Daniel J. Freeman, Kevin Yang, Ryan Wurz, Longbin Liu, Raju Subramanian, Kristin L. Andrews, Ling Wang, Liping H. Pettus, Nancy Zhang |
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| Rok vydání: | 2012 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Antineoplastic Agents Pharmacology Crystallography X-Ray Biochemistry Mice Phosphatidylinositol 3-Kinases Structure-Activity Relationship In vivo Cell Line Tumor Neoplasms Drug Discovery Animals Humans Structure–activity relationship Phosphorylation Protein Kinase Inhibitors Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Sulfonamides Binding Sites Phosphoinositide 3-kinase biology Triazines Akt/PKB signaling pathway Chemistry TOR Serine-Threonine Kinases Cellular Assay Organic Chemistry Rats Molecular Docking Simulation biology.protein Molecular Medicine Female Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:5714-5720 |
| ISSN: | 0960-894X |
| Popis: | Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL). |
| Databáze: | OpenAIRE |
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