6TWA

Human CD73 (ecto 5'-nucleotidase) in complex with PSB12646 (an AOPCP derivative, compound 20 in publication) in the closed state

Summary for 6TWA

• Entry DOI: 10.2210/pdb6twa/pdb
• Descriptor: 5'-nucleotidase, ZINC ION, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-azanyl-2-diazanyl-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]methylphosphonic acid, ... (5 entities in total)
• Functional Keywords: nucleotide analog, en, 5nt, complex, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 59886.56

Authors

Pippel, J.,Strater, N. (deposition date: 2020-01-12, release date: 2020-02-19, Last modification date: 2024-10-23)

Primary citation

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.
2-Substituted alpha , beta-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes.
J.Med.Chem., 63:2941-2957, 2020

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'--[(phosphonomethyl)phosphonic acid] (, ) being the most potent inhibitors with 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 () 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 -substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.

PubMed: 32045236
DOI: 10.1021/acs.jmedchem.9b01611

Experimental method

X-RAY DIFFRACTION (2 Å)