Rageot, Denise, Bohnacker, Thomas, Melone, Anna, Langlois, Jean-Baptiste, Borsari, Chiara, Hillmann, Petra, Sele, Alexander M., Beaufils, Florent, Zvelebil, Marketa, Hebeisen, Paul, Löscher, Wolfgang, Burke, John, Fabbro, Doriano and Wymann, Matthias P. (2018) 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, 61 (22). pp. 10084-10105. ISSN 0022-2623

Abstract

Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 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 inhibited tumor growth significantly. Moreover, PQR620 attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 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.

Item Type:	Article
Keywords:	PI3K inhibitor - mTOR inhibitor
Date Deposited:	08 Dec 2018 00:45
Last Modified:	08 Dec 2018 00:45
URI:	https://oak.novartis.com/id/eprint/38485