2. Academic Validation
  3. Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes

  • J Med Chem. 2023 Jul 13;66(13):9095-9119. doi: 10.1021/acs.jmedchem.3c00705.
Simone Bonazzi 1,  Audrey Gray 2,  Noel M Thomsen 1,  Jonathan Biag 2,  Nancy Labbe-Giguere 1,  Erin P Keaney 1,  Hasnain A Malik 1,  Yingchuan Sun 1,  Jill Nunez 1,  Rajeshri G Karki 1,  Mark Knapp 3,  Robert Elling 3,  John Fuller 4,  Gwynn Pardee 4,  Lucas Craig 2,  Ketthsy Capre 2,  Sarah Salas 2,  Aakruti Gorde 2,  Guiqing Liang 5,  Danuta Lubicka 6,  Stephanie M McTighe 2,  Carleton Goold 2,  Shanming Liu 7,  Lin Deng 5,  Jin Hong 8,  Alexander Fekete 8,  Pascal Stadelmann 9,  Wilfried Frieauff 9,  Azeddine Elhajouji 9,  Daniel Bauer 9,  Andreas Lerchner 10,  Branko Radetich 1,  Pascal Furet 10,  Grazia Piizzi 1,  Doug Burdette 5,  Christopher J Wilson 2,  Stefan Peukert 1,  Lawrence G Hamann 1,  Leon O Murphy 7,  Daniel Curtis 2
Affiliations

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 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5959 Horton St, Emeryville, California 94608, United States.
  • 4 Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 5959 Horton St, Emeryville, California 94608, United States.
  • 5 Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 6 Global Drug Development/Technical Research and Development, Novartis Institutes for BioMedical Research, 700 Main Street, Cambridge, Massachusetts 02139, United States.
  • 7 Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
  • 8 Preclinical Safety, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 9 Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 28, 4056 Basel, Switzerland.
  • 10 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabrikstrasse 22, 4056 Basel, Switzerland.
PMID: 37399505 DOI: 10.1021/acs.jmedchem.3c00705
Abstract

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR Inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR Inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

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