Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders

  • J Med Chem. 2020 Feb 13;63(3):1068-1083. doi: 10.1021/acs.jmedchem.9b01398.
Simone Bonazzi  1 ,  Carleton P Goold  2 ,  Audrey Gray  2 ,  Noel M Thomsen  1 ,  Jill Nunez  1 ,  Rajeshri G Karki  1 ,  Aakruti Gorde  2 ,  Jonathan D Biag  2 ,  Hasnain A Malik  1 ,  Yingchuan Sun  1 ,  Guiqing Liang  3 ,  Danuta Lubicka  4 ,  Sarah Salas  2 ,  Nancy Labbe-Giguere  1 ,  Erin P Keaney  1 ,  Stephanie McTighe  2 ,  Shanming Liu  5 ,  Lin Deng  3 ,  Grazia Piizzi  1 ,  Franco Lombardo  3 ,  Doug Burdette  3 ,  Jean-Cosme Dodart  2 ,  Christopher J Wilson  2 ,  Stefan Peukert  1 ,  Daniel Curtis  2 ,  Lawrence G Hamann  1 ,  Leon O Murphy  5
Affiliations
  • 1. Global Discovery Chemistry , Novartis Institutes for BioMedical Research , 181 Massachusetts Ave , Cambridge , Massachusetts 02139 , United States.
  • 2. Neuroscience , Novartis Institutes for BioMedical Research , 22 Windsor Street , Cambridge , Massachusetts 02139 , United States.
  • 3. Pharmacokinetic Sciences , Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States.
  • 4. Global Drug Development/Technical Research and Development , Novartis Institutes for BioMedical Research , 700 Main Street , Cambridge , Massachusetts 02139 , United States.
  • 5. Chemical Biology and Therapeutics , Novartis Institutes for BioMedical Research , 181 Massachusetts Ave , Cambridge , Massachusetts 02139 , United States.
PMID: 31955578 DOI: 10.1021/acs.jmedchem.9b01398
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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