化学
取代基
立体化学
效力
亚甲基
5'-核苷酸酶
结构-活动关系
非竞争性抑制
腺苷
生物化学
变构调节
核苷酸酶
嘌呤
核苷酸
酶
结合位点
体外
药物化学
作者
Sanjay Bhattarai,Jan Pippel,Emma Rose Scaletti,Riham M. Idris,Marianne Freundlieb,Georg Rolshoven,Christian Renn,Sang-Yong Tom Lee,Aliaa Abdelrahman,Herbert Zimmermann,Ali El-Tayeb,Christa E. Müller,Norbert Sträter
标识
DOI:10.1021/acs.jmedchem.9b01611
摘要
CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5'-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
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