Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders
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. Giv...
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| Published in | Journal of medicinal chemistry Vol. 63; no. 3; pp. 1068 - 1083 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
13.02.2020
Amer Chemical Soc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0022-2623 1520-4804 1520-4804 |
| DOI | 10.1021/acs.jmedchem.9b01398 |
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| Abstract | 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. |
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| AbstractList | 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. 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 , a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 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. 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.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. |
| Author | Gray, Audrey Lombardo, Franco Piizzi, Grazia Karki, Rajeshri G Peukert, Stefan Goold, Carleton P Deng, Lin Thomsen, Noel M Labbe-Giguere, Nancy Hamann, Lawrence G Nunez, Jill Gorde, Aakruti Sun, Yingchuan Liu, Shanming Burdette, Doug Liang, Guiqing Curtis, Daniel Lubicka, Danuta Biag, Jonathan D Malik, Hasnain A Murphy, Leon O Wilson, Christopher J Keaney, Erin P McTighe, Stephanie Bonazzi, Simone Dodart, Jean-Cosme Salas, Sarah |
| AuthorAffiliation | Global Drug Development/Technical Research and Development Global Discovery Chemistry Neuroscience Chemical Biology and Therapeutics Pharmacokinetic Sciences |
| AuthorAffiliation_xml | – name: Pharmacokinetic Sciences – name: Global Discovery Chemistry – name: Chemical Biology and Therapeutics – name: Global Drug Development/Technical Research and Development – name: Neuroscience |
| Author_xml | – sequence: 1 givenname: Simone orcidid: 0000-0001-5698-3155 surname: Bonazzi fullname: Bonazzi, Simone email: simone.bonazzi@novartis.com organization: Global Discovery Chemistry – sequence: 2 givenname: Carleton P surname: Goold fullname: Goold, Carleton P organization: Neuroscience – sequence: 3 givenname: Audrey surname: Gray fullname: Gray, Audrey organization: Neuroscience – sequence: 4 givenname: Noel M surname: Thomsen fullname: Thomsen, Noel M organization: Global Discovery Chemistry – sequence: 5 givenname: Jill surname: Nunez fullname: Nunez, Jill organization: Global Discovery Chemistry – sequence: 6 givenname: Rajeshri G orcidid: 0000-0003-2210-5789 surname: Karki fullname: Karki, Rajeshri G organization: Global Discovery Chemistry – sequence: 7 givenname: Aakruti surname: Gorde fullname: Gorde, Aakruti organization: Neuroscience – sequence: 8 givenname: Jonathan D surname: Biag fullname: Biag, Jonathan D organization: Neuroscience – sequence: 9 givenname: Hasnain A surname: Malik fullname: Malik, Hasnain A organization: Global Discovery Chemistry – sequence: 10 givenname: Yingchuan surname: Sun fullname: Sun, Yingchuan organization: Global Discovery Chemistry – sequence: 11 givenname: Guiqing surname: Liang fullname: Liang, Guiqing organization: Pharmacokinetic Sciences – sequence: 12 givenname: Danuta surname: Lubicka fullname: Lubicka, Danuta organization: Global Drug Development/Technical Research and Development – sequence: 13 givenname: Sarah surname: Salas fullname: Salas, Sarah organization: Neuroscience – sequence: 14 givenname: Nancy surname: Labbe-Giguere fullname: Labbe-Giguere, Nancy organization: Global Discovery Chemistry – sequence: 15 givenname: Erin P surname: Keaney fullname: Keaney, Erin P organization: Global Discovery Chemistry – sequence: 16 givenname: Stephanie surname: McTighe fullname: McTighe, Stephanie organization: Neuroscience – sequence: 17 givenname: Shanming surname: Liu fullname: Liu, Shanming organization: Chemical Biology and Therapeutics – sequence: 18 givenname: Lin surname: Deng fullname: Deng, Lin organization: Pharmacokinetic Sciences – sequence: 19 givenname: Grazia surname: Piizzi fullname: Piizzi, Grazia organization: Global Discovery Chemistry – sequence: 20 givenname: Franco surname: Lombardo fullname: Lombardo, Franco organization: Pharmacokinetic Sciences – sequence: 21 givenname: Doug surname: Burdette fullname: Burdette, Doug organization: Pharmacokinetic Sciences – sequence: 22 givenname: Jean-Cosme surname: Dodart fullname: Dodart, Jean-Cosme organization: Neuroscience – sequence: 23 givenname: Christopher J surname: Wilson fullname: Wilson, Christopher J organization: Neuroscience – sequence: 24 givenname: Stefan surname: Peukert fullname: Peukert, Stefan organization: Global Discovery Chemistry – sequence: 25 givenname: Daniel surname: Curtis fullname: Curtis, Daniel organization: Neuroscience – sequence: 26 givenname: Lawrence G orcidid: 0000-0002-8997-7912 surname: Hamann fullname: Hamann, Lawrence G organization: Global Discovery Chemistry – sequence: 27 givenname: Leon O surname: Murphy fullname: Murphy, Leon O organization: Chemical Biology and Therapeutics |
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| Title | Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders |
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