生物利用度
化学
药理学
激酶
赫尔格
PI3K/AKT/mTOR通路
mTOR抑制剂的发现与发展
卵巢癌
铅化合物
药代动力学
癌症
体外
信号转导
内科学
医学
生物化学
钾通道
作者
Dinesh Mahajan,Somdutta Sen,Bilash Kuila,Amit Sharma,Reena Arora,Milind Sagar,Amal Ray Mahapatra,Lalita Babasaheb Gawade,Sundeep Dugar
标识
DOI:10.1021/acs.jmedchem.0c01061
摘要
Herein, we report the identification and preclinical profile of a lead compound 10, (SPR519) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC50 of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48 μM), and SKOV3 (0.50 μM). When administrated orally, it shows a considerably high plasma exposure (area under curve: 26,858 nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified lead compound demonstrates significant efficacy and bioavailability in ovarian and colon cancer xenograft models when evaluated for dose-ranging efficacy studies, at a dose as low as 2.5 mg/kg.
科研通智能强力驱动
Strongly Powered by AbleSci AI