Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders
| Autor: | Noel Marie-France Thomsen, Simone Bonazzi, Stephanie M. McTighe, Guiqing Liang, Danuta Lubicka, Sarah Salas, Jill Nunez, Franco Lombardo, Rajeshri Ganesh Karki, Audrey Gray, Stefan Peukert, Doug Burdette, Jean-Cosme Dodart, Leon Murphy, Grazia Piizzi, Carleton Goold, Labbe-Giguere Nancy, Erin P. Keaney, Jonathan D. Biag, Christine D. Wilson, Aakruti Gorde, Lawrence G. Hamann, Yingchuan Sun, Lin Deng, Hasnain A. Malik, Daniel Curtis, Shanming Liu |
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| Rok vydání: | 2020 |
| Předmět: |
Purine
Male Cell Central nervous system 01 natural sciences Tuberous Sclerosis Complex 1 Protein 03 medical and health sciences chemistry.chemical_compound Seizures Drug Discovery medicine Animals Humans Mechanistic target of rapamycin Protein Kinase Inhibitors PI3K/AKT/mTOR pathway 030304 developmental biology Mice Knockout Neurons 0303 health sciences Everolimus Binding Sites biology Drug discovery TOR Serine-Threonine Kinases Brain 0104 chemical sciences Rats Mice Inbred C57BL 010404 medicinal & biomolecular chemistry Thiazoles medicine.anatomical_structure Pyrimidines chemistry Cancer research biology.protein Molecular Medicine Anticonvulsants TSC1 medicine.drug Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 63(3) |
| ISSN: | 1520-4804 |
| Popis: | Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS. |
| Databáze: | OpenAIRE |
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