Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders
Denise Rageot
1
,
Thomas Bohnacker
1
,
Anna Melone
1
,
Jean-Baptiste Langlois
1
,
Chiara Borsari
1
,
Petra Hillmann
2
,
Alexander M Sele
1
,
Florent Beaufils
1
,
Marketa Zvelebil
1
,
Paul Hebeisen
2
,
Wolfgang Löscher
3
,
John E. Burke
4
,
Doriano Fabbro
2
,
Matthias Wymann
1
2
PIQUR Therapeutics AG, Hochbergerstrasse 60, 4057 Basel, Switzerland
|
Publication type: Journal Article
Publication date: 2018-10-25
scimago Q1
wos Q1
SJR: 1.801
CiteScore: 11.5
Impact factor: 6.8
ISSN: 00222623, 15204804
PubMed ID:
30359003
Drug Discovery
Molecular Medicine
Abstract
Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
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72
Total citations:
72
Citations from 2025:
8
(11.11%)
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Rageot D. et al. Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 22. pp. 10084-10105.
GOST all authors (up to 50)
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Rageot D., Bohnacker T., Melone A., Langlois J., Borsari C., Hillmann P., Sele A. M., Beaufils F., Zvelebil M., Hebeisen P., Löscher W., Burke J. E., Fabbro D., Wymann M. Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 22. pp. 10084-10105.
Cite this
RIS
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TY - JOUR
DO - 10.1021/acs.jmedchem.8b01262
UR - https://doi.org/10.1021/acs.jmedchem.8b01262
TI - Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders
T2 - Journal of Medicinal Chemistry
AU - Rageot, Denise
AU - Bohnacker, Thomas
AU - Melone, Anna
AU - Langlois, Jean-Baptiste
AU - Borsari, Chiara
AU - Hillmann, Petra
AU - Sele, Alexander M
AU - Beaufils, Florent
AU - Zvelebil, Marketa
AU - Hebeisen, Paul
AU - Löscher, Wolfgang
AU - Burke, John E.
AU - Fabbro, Doriano
AU - Wymann, Matthias
PY - 2018
DA - 2018/10/25
PB - American Chemical Society (ACS)
SP - 10084-10105
IS - 22
VL - 61
PMID - 30359003
SN - 0022-2623
SN - 1520-4804
ER -
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BibTex (up to 50 authors)
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@article{2018_Rageot,
author = {Denise Rageot and Thomas Bohnacker and Anna Melone and Jean-Baptiste Langlois and Chiara Borsari and Petra Hillmann and Alexander M Sele and Florent Beaufils and Marketa Zvelebil and Paul Hebeisen and Wolfgang Löscher and John E. Burke and Doriano Fabbro and Matthias Wymann},
title = {Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {oct},
url = {https://doi.org/10.1021/acs.jmedchem.8b01262},
number = {22},
pages = {10084--10105},
doi = {10.1021/acs.jmedchem.8b01262}
}
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MLA
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Rageot, Denise, et al. “Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.” Journal of Medicinal Chemistry, vol. 61, no. 22, Oct. 2018, pp. 10084-10105. https://doi.org/10.1021/acs.jmedchem.8b01262.