作者
Neil P. Grimster,Lakshmaiah Gingipalli,Amber Balazs,Bernard Barlaam,Scott Boiko,Scott Boyd,Hannah Dry,Frederick W. Goldberg,Tim Ikeda,Tony G. Johnson,Sameer Kawatkar,Paul D. Kemmitt,Scott G. Lamont,Olivier Lorthioir,Adelphe Mfuh,Joe Patel,Andy Pike,Jon Read,Romulo H. Romero,Ujjal Sarkar,Sha Li,Iain Simpson,Kun Song,Qibin Su,Haixia Wang,David Watson,Allan Wu,Troy E. Zehnder,Xiaolan Zheng,Shao‐Lu Li,Zhiqiang Dong,Dejun Yang,Yue Song,Peng Wang,Xuemei Liu,James E. Dowling,Scott D. Edmondson
摘要
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.