Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA.
J Med Chem. 2009 Dec 24;52(24):7942-5. doi: 10.1021/jm901415x.
Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
通过用桥环吗啉取代吡唑并嘧啶抑制剂中的吗啉，实现了对 mTOR 靶向选择性的显著改善。制备了具有亚纳摩尔 mTOR IC（50）值和高达 26000 倍对 PI3Kalpha 选择性的类似物。手性吗啉给出了具有不同选择性和效力特征的抑制剂的对映体。分子建模表明，PI3K 和 mTOR 之间（Phe961Leu）的单个氨基酸差异导致了在 mTOR 中创建一个可以容纳桥环吗啉的更深口袋，从而产生了深刻的选择性。
