PMID- 31465220
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20211204
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 62
IP  - 18
DP  - 2019 Sep 26
TI  - A Conformational Restriction Strategy for the Identification of a Highly 
      Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor.
PG  - 8609-8630
LID - 10.1021/acs.jmedchem.9b00972 [doi]
AB  - The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and 
      tumor progression and is an attractive target for cancer treatment. 
      ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome 
      limitations of rapamycin derivatives in a wide range of malignancies. Herein, we 
      exploit a conformational restriction approach to explore a novel chemical space 
      for the generation of TORKi. Structure-activity relationship (SAR) studies led to 
      the identification of compound 12b with a  approximately 450-fold selectivity for mTOR over 
      class I PI3K isoforms. Pharmacokinetic studies in male Sprague Dawley rats 
      highlighted a good exposure after oral dosing and a minimum brain penetration. 
      CYP450 reactive phenotyping pointed out the high metabolic stability of 12b. 
      These results identify the tricyclic pyrimido-pyrrolo-oxazine moiety as a novel 
      scaffold for the development of highly selective mTOR inhibitors for cancer 
      treatment.
FAU - Borsari, Chiara
AU  - Borsari C
AUID- ORCID: 0000-0002-4688-8362
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Rageot, Denise
AU  - Rageot D
AUID- ORCID: 0000-0002-2833-5481
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Dall'Asen, Alix
AU  - Dall'Asen A
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
FAU - Bohnacker, Thomas
AU  - Bohnacker T
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Melone, Anna
AU  - Melone A
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Sele, Alexander M
AU  - Sele AM
AUID- ORCID: 0000-0002-4903-7934
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Jackson, Eileen
AU  - Jackson E
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Langlois, Jean-Baptiste
AU  - Langlois JB
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Beaufils, Florent
AU  - Beaufils F
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
FAU - Hebeisen, Paul
AU  - Hebeisen P
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
FAU - Fabbro, Doriano
AU  - Fabbro D
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
FAU - Hillmann, Petra
AU  - Hillmann P
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
FAU - Wymann, Matthias P
AU  - Wymann MP
AUID- ORCID: 0000-0003-3349-4281
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190911
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Oxazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidinones)
RN  - 0 (Pyrroles)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adenosine Triphosphate/chemistry
MH  - Animals
MH  - Antineoplastic Agents/chemistry/pharmacokinetics
MH  - Dogs
MH  - Drug Design
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Kinetics
MH  - Male
MH  - Mice
MH  - Molecular Conformation
MH  - Neoplasms/drug therapy
MH  - Oxazines/*chemistry/pharmacokinetics
MH  - Protein Kinase Inhibitors/*chemistry/pharmacokinetics
MH  - Pyrimidinones/*chemistry/pharmacokinetics
MH  - Pyrroles/*chemistry/pharmacokinetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/chemistry
EDAT- 2019/08/30 06:00
MHDA- 2020/06/23 06:00
CRDT- 2019/08/30 06:00
PHST- 2019/08/30 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/08/30 06:00 [entrez]
AID - 10.1021/acs.jmedchem.9b00972 [doi]
PST - ppublish
SO  - J Med Chem. 2019 Sep 26;62(18):8609-8630. doi: 10.1021/acs.jmedchem.9b00972. Epub 
      2019 Sep 11.