PMID- 37399505
OWN - NLM
STAT- MEDLINE
DCOM- 20230714
LR  - 20230718
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 66
IP  - 13
DP  - 2023 Jul 13
TI  - Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS 
      Syndromes.
PG  - 9095-9119
LID - 10.1021/acs.jmedchem.3c00705 [doi]
AB  - 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.
FAU - Bonazzi, Simone
AU  - Bonazzi S
AUID- ORCID: 0000-0001-5698-3155
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Gray, Audrey
AU  - Gray A
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Thomsen, Noel M
AU  - Thomsen NM
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Biag, Jonathan
AU  - Biag J
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Labbe-Giguere, Nancy
AU  - Labbe-Giguere N
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Keaney, Erin P
AU  - Keaney EP
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Malik, Hasnain A
AU  - Malik HA
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Sun, Yingchuan
AU  - Sun Y
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Nunez, Jill
AU  - Nunez J
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Karki, Rajeshri G
AU  - Karki RG
AUID- ORCID: 0000-0003-2210-5789
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Knapp, Mark
AU  - Knapp M
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5959 
      Horton St, Emeryville, California 94608, United States.
FAU - Elling, Robert
AU  - Elling R
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5959 
      Horton St, Emeryville, California 94608, United States.
FAU - Fuller, John
AU  - Fuller J
AD  - Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 
      5959 Horton St, Emeryville, California 94608, United States.
FAU - Pardee, Gwynn
AU  - Pardee G
AD  - Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 
      5959 Horton St, Emeryville, California 94608, United States.
FAU - Craig, Lucas
AU  - Craig L
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Capre, Ketthsy
AU  - Capre K
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Salas, Sarah
AU  - Salas S
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Gorde, Aakruti
AU  - Gorde A
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Liang, Guiqing
AU  - Liang G
AD  - Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 
      Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
FAU - Lubicka, Danuta
AU  - Lubicka D
AD  - Global Drug Development/Technical Research and Development, Novartis Institutes 
      for BioMedical Research, 700 Main Street, Cambridge, Massachusetts 02139, United 
      States.
FAU - McTighe, Stephanie M
AU  - McTighe SM
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Goold, Carleton
AU  - Goold C
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Liu, Shanming
AU  - Liu S
AD  - Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 
      181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Deng, Lin
AU  - Deng L
AD  - Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 
      Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
FAU - Hong, Jin
AU  - Hong J
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research, 250 
      Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
FAU - Fekete, Alexander
AU  - Fekete A
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research, 250 
      Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
FAU - Stadelmann, Pascal
AU  - Stadelmann P
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 
      28, 4056 Basel, Switzerland.
FAU - Frieauff, Wilfried
AU  - Frieauff W
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 
      28, 4056 Basel, Switzerland.
FAU - Elhajouji, Azeddine
AU  - Elhajouji A
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 
      28, 4056 Basel, Switzerland.
FAU - Bauer, Daniel
AU  - Bauer D
AUID- ORCID: 0000-0001-5751-2988
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 
      28, 4056 Basel, Switzerland.
FAU - Lerchner, Andreas
AU  - Lerchner A
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 
      Fabrikstrasse 22, 4056 Basel, Switzerland.
FAU - Radetich, Branko
AU  - Radetich B
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Furet, Pascal
AU  - Furet P
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 
      Fabrikstrasse 22, 4056 Basel, Switzerland.
FAU - Piizzi, Grazia
AU  - Piizzi G
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Burdette, Doug
AU  - Burdette D
AD  - Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 
      Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
FAU - Wilson, Christopher J
AU  - Wilson CJ
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
FAU - Peukert, Stefan
AU  - Peukert S
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Hamann, Lawrence G
AU  - Hamann LG
AD  - Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 
      Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Murphy, Leon O
AU  - Murphy LO
AD  - Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 
      181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
FAU - Curtis, Daniel
AU  - Curtis D
AD  - Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, 
      Cambridge, Massachusetts 02139, United States.
LA  - eng
PT  - Journal Article
DEP - 20230703
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - W36ZG6FT64 (Sirolimus)
RN  - 0 (MTOR Inhibitors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Sirolimus
MH  - *MTOR Inhibitors
MH  - Syndrome
MH  - Central Nervous System/metabolism
MH  - Brain/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Adenosine Triphosphate
EDAT- 2023/07/03 19:08
MHDA- 2023/07/14 13:06
CRDT- 2023/07/03 15:53
PHST- 2023/07/14 13:06 [medline]
PHST- 2023/07/03 19:08 [pubmed]
PHST- 2023/07/03 15:53 [entrez]
AID - 10.1021/acs.jmedchem.3c00705 [doi]
PST - ppublish
SO  - J Med Chem. 2023 Jul 13;66(13):9095-9119. doi: 10.1021/acs.jmedchem.3c00705. Epub 
      2023 Jul 3.