化学
小分子
活动站点
水解酶
药物发现
布鲁顿酪氨酸激酶
生物化学
结构-活动关系
酶
计算生物学
立体化学
信号转导
生物
酪氨酸激酶
体外
作者
Esra Balıkçı,Anne-Sophie M. C. Marques,Larry A. Bauer,Raina Seupel,James M. Bennett,Brigitt Raux,Karly A. Buchan,Klemensas Šimelis,Usha Singh,Catherine Rogers,Jennifer A. Ward,Carol Cheng,Tamás Szommer,Kira Schützenhofer,J.M. Elkins,David L. Sloman,Ivan Ahel,Oleg Fedorov,Paul E. Brennan,Kilian Huber
标识
DOI:10.1021/acs.jmedchem.4c00072
摘要
Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure–activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.
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