期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 6, 页码 2941-2957出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01611
关键词
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资金
- Ministry for Innovation, Science, Research and Technology of the State of North-Rhine-Westfalia (NRW International Graduate Research School BIOTECH-PHARMA)
- Deutsche Forschungsgemeinschaft [SFB1328, SFB 1052]
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 alpha,beta-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 K-i 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 N-6-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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