2-Substituted α,β-Methylene-ADP Derivatives : Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of medicinal chemistry - 63(2020), 6 vom: 26. März, Seite 2941-2957 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bhattarai, Sanjay [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.09.2020 Date Revised 02.09.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.9b01611 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM306396548 |
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| 245 | 1 | 0 | |a 2-Substituted α,β-Methylene-ADP Derivatives |b Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes |
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| 520 | |a 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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| 700 | 1 | |a Freundlieb, Marianne |e verfasserin |4 aut | |
| 700 | 1 | |a Rolshoven, Georg |e verfasserin |4 aut | |
| 700 | 1 | |a Renn, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Sang-Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Abdelrahman, Aliaa |e verfasserin |4 aut | |
| 700 | 1 | |a Zimmermann, Herbert |e verfasserin |4 aut | |
| 700 | 1 | |a El-Tayeb, Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Christa E |e verfasserin |4 aut | |
| 700 | 1 | |a Sträter, Norbert |e verfasserin |4 aut | |
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