Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders
Simone Bonazzi, Carleton P. Goold, Audrey Gray, Noel M. Thomsen, Jill Nunez, Rajeshri G. Karki, Aakruti Gorde, Jonathan Biag, Hasnain A. Malik, Yingchuan Sun, Guiqing Liang, Danuta Lubicka, Sarah Salas, Nancy Labbé-Giguère, Erin P. Keaney, Stephanie M. McTighe, Shanming Liu, Linhong Deng, Grazia Piizzi, Franco Lombardo, Doug Burdette, Jean‐Cosme Dodart, Christopher J. Wilson, Stefan Peukert, Daniel Curtis, Lawrence G. Hamann, Leon O. Murphy
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.