2‑Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes

• Published in: Journal of medicinal chemistry Vol. 63; no. 6; pp. 2941 - 2957
• Main Authors: Bhattarai, Sanjay, Pippel, Jan, Scaletti, Emma, Idris, Riham, Freundlieb, Marianne, Rolshoven, Georg, Renn, Christian, Lee, Sang-Yong, Abdelrahman, Aliaa, Zimmermann, Herbert, El-Tayeb, Ali, Müller, Christa E, Sträter, Norbert
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.03.2020; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ECTO-5'-NUCLEOTIDASE; REFINEMENT; IMMUNITY; MAXIMUM-LIKELIHOOD; ANALOGS; CRYSTAL-STRUCTURE; NUCLEOSIDES; ADENOSINE; AGONISTS; INSIGHTS
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01611

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.