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

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.