PMID- 31244112
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20211204
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 62
IP  - 13
DP  - 2019 Jul 11
TI  - (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine 
      (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of 
      Class I PI3K and mTOR Kinase.
PG  - 6241-6261
LID - 10.1021/acs.jmedchem.9b00525 [doi]
AB  - The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) 
      pathway is frequently overactivated in cancer, and drives cell growth, 
      proliferation, survival, and metastasis. Here, we report a structure-activity 
      relationship study, which led to the discovery of a drug-like adenosine 
      5'-triphosphate-site PI3K/mTOR kinase inhibitor: 
      (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine 
      (PQR530, compound 6), which qualifies as a clinical candidate due to its potency 
      and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, 
      including brain penetration. Compound 6 showed excellent selectivity over a wide 
      panel of kinases and an excellent selectivity against unrelated receptor enzymes 
      and ion channels. Moreover, compound 6 prevented cell growth in a cancer cell 
      line panel. The preclinical in vivo characterization of compound 6 in an OVCAR-3 
      xenograft model demonstrated good oral bioavailability, excellent brain 
      penetration, and efficacy. Initial toxicity studies in rats and dogs qualify 6 
      for further development as a therapeutic agent in oncology.
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 - Bohnacker, Thomas
AU  - Bohnacker T
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Keles, Erhan
AU  - Keles E
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - McPhail, Jacob A
AU  - McPhail JA
AD  - Department of Biochemistry and Microbiology , University of Victoria , Victoria , 
      British Columbia V8W 2Y2 , Canada.
FAU - Hoffmann, Reece M
AU  - Hoffmann RM
AD  - Department of Biochemistry and Microbiology , University of Victoria , Victoria , 
      British Columbia V8W 2Y2 , Canada.
FAU - Melone, Anna
AU  - Melone A
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
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 - Sriramaratnam, Rohitha
AU  - Sriramaratnam R
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 - Beaufils, Florent
AU  - Beaufils F
AD  - Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , 
      Switzerland.
FAU - Hebeisen, Paul
AU  - Hebeisen P
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.
FAU - Fabbro, Doriano
AU  - Fabbro D
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.
FAU - Hillmann, Petra
AU  - Hillmann P
AD  - PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.
FAU - Burke, John E
AU  - Burke JE
AUID- ORCID: 0000-0001-7904-9859
AD  - Department of Biochemistry and Microbiology , University of Victoria , Victoria , 
      British Columbia V8W 2Y2 , Canada.
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 - 20190620
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Aminopyridines)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Morpholines)
RN  - 0 (PQR530)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Triazines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Aminopyridines/chemical synthesis/metabolism/*pharmacology
MH  - Animals
MH  - Antineoplastic Agents/chemical synthesis/metabolism/*pharmacology
MH  - Brain/metabolism
MH  - Cell Line, Tumor
MH  - Dogs
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Microsomes, Liver/metabolism
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - Morpholines/chemical synthesis/metabolism/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors/chemical synthesis/metabolism/*pharmacology
MH  - Protein Binding
MH  - Pyridines/chemical synthesis/metabolism/*pharmacology
MH  - Rats, Wistar
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Triazines/chemical synthesis/metabolism/*pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2019/06/28 06:00
MHDA- 2020/06/23 06:00
CRDT- 2019/06/28 06:00
PHST- 2019/06/28 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/06/28 06:00 [entrez]
AID - 10.1021/acs.jmedchem.9b00525 [doi]
PST - ppublish
SO  - J Med Chem. 2019 Jul 11;62(13):6241-6261. doi: 10.1021/acs.jmedchem.9b00525. Epub 
      2019 Jun 20.