Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.
PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
J Med Chem. 2018 Nov 21;61(22):10084-10105. doi: 10.1021/acs.jmedchem.8b01262. Epub 2018 Nov 14.
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) in plasma and brain was reached after 30 min, with a half-life ( t) > 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.
雷帕霉素靶蛋白（mTOR）促进细胞增殖、生长和存活，在许多肿瘤和中枢神经系统疾病中过度激活。PQR620（3）是一种新型、有效、选择性和可穿透脑屏障的 mTORC1/2 激酶抑制剂。PQR620（3）对 mTOR 表现出优异的选择性，超过了 PI3K 和蛋白激酶，并且在 66 种癌细胞系面板中有效地阻止了癌细胞生长。在 C57BL/6J 和 Sprague-Dawley 小鼠中，血浆和脑中的最大浓度（C）在 30 分钟后达到，半衰期（t）>5 小时。在卵巢癌小鼠异种移植模型（OVCAR-3）中，每日给予 PQR620（3）可显著抑制肿瘤生长。此外，PQR620（3）可减轻结节性硬化症（TSC）小鼠模型中的癫痫发作。总之，PQR620（3）可有效且选择性地抑制 mTOR 激酶，在体外和体内均具有抗肿瘤作用，并由于其脑/血浆分布比，有望在中枢神经系统适应症中具有优势。
