Download Mendeley2-Substituted alpha , beta-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes.
Bhattarai, S., Pippel, J., Scaletti, E., Idris, R., Freundlieb, M., Rolshoven, G., Renn, C., Lee, S.Y., Abdelrahman, A., Zimmermann, H., El-Tayeb, A., Muller, C.E., Strater, N.(2020) J Med Chem 63: 2941-2957
- PubMed: 32045236
- DOI: https://doi.org/10.1021/acs.jmedchem.9b01611
- Primary Citation of Related Structures:
6TVE, 6TVG, 6TVX, 6TW0, 6TWA, 6TWF - PubMed Abstract:
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 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.
Organizational Affiliation:
PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
