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.

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.

• Authors: Denise Rageot, Thomas Bohnacker, Anna Melone, Jean-Baptiste Langlois, Chiara Borsari, Petra Hillmann, Alexander M Sele, Florent Beaufils, Marketa Zvelebil, Paul Hebeisen, Wolfgang Löscher, John Burke, Doriano Fabbro, Matthias P Wymann
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 22 Pg. 10084-10105 (11 21 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30359003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Azabicyclo Compounds
• Pyridines
• Triazines
• pqr620
• Phosphatidylinositol 3-Kinases
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2

Topics

• Animals
• Azabicyclo Compounds (metabolism, pharmacology, therapeutic use)
• Blood-Brain Barrier (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)
• Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors)
• Mice
• Models, Molecular
• Phosphatidylinositol 3-Kinases (chemistry, metabolism)
• Protein Conformation
• Pyridines (metabolism, pharmacology, therapeutic use)
• Rats
• Seizures (drug therapy)
• Triazines (metabolism, pharmacology, therapeutic use)