Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 22, Pages 10084-10105Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01262
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Funding
- Swiss Commission for Technology and Innovation (CTI) by PFLS-LS [14032.1, 15811.2, 17241.1]
- Stiftung fur Krebsbekampfung grant [341]
- Swiss National Science Foundation [310030_153211, 316030_133860, 310030B_138659]
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [675392]
- Cancer Research Society [CRS-22641]
- Epilepsy Foundation of America
- Swiss National Science Foundation (SNF) [310030_153211, 316030_133860] Funding Source: Swiss National Science Foundation (SNF)
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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 (C-max) in plasma and brain was reached after 30 min, with a half-life (t(1/2)) > 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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