2. Academic Validation
  3. Structure-Activity Relationship of 3-Methylcytidine-5'-α,β-methylenediphosphates as CD73 Inhibitors

Structure-Activity Relationship of 3-Methylcytidine-5'-α,β-methylenediphosphates as CD73 Inhibitors

  • J Med Chem. 2022 Feb 10;65(3):2409-2433. doi: 10.1021/acs.jmedchem.1c01852.
Mirko Scortichini 1,  Riham Mohammed Idris 2,  Susanne Moschütz 3,  Antje Keim 3,  Veronica Salmaso 1,  Clemens Dobelmann 4,  Paola Oliva 1,  Karolina Losenkova 5,  Heikki Irjala 6,  Samuli Vaittinen 7,  Jouko Sandholm 8,  Gennady G Yegutkin 5,  Norbert Sträter 3,  Anna Junker 4,  Christa E Müller 2,  Kenneth A Jacobson 1
Affiliations

Affiliations

  • 1 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 2 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 3 Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany.
  • 4 European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstrasse 15, D-48149 Münster, Germany.
  • 5 Medicity Research Laboratory, University of Turku, 20520 Turku, Finland.
  • 6 Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital and Turku University, 20520 Turku, Finland.
  • 7 Department of Pathology, Turku University Hospital and Turku University, 20520 Turku, Finland.
  • 8 Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
PMID: 35080883 DOI: 10.1021/acs.jmedchem.1c01852
Abstract

We recently reported N4-substituted 3-methylcytidine-5'-α,β-methylenediphosphates as CD73 inhibitors, potentially useful in Cancer Immunotherapy. We now expand the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 16; Ki = 0.673 nM) and 4-iodo (MRS4620 18; Ki = 0.436 nM) substitution of the N4-benzyloxy group decreased Ki by ∼20-fold. Primary alkylamine derivatives coupled through a p-amido group with a varying methylene chain length (24 and 25) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformational adaptation, and the benzyloxyimino group (E configuration) binds to the same region (between the C-terminal and N-terminal domains) as N4-benzyl groups in adenine inhibitors. Molecular dynamics identified stabilizing interactions and predicted conformational diversity. Thus, by N4-benzyloxy substitution, we have greatly enhanced the inhibitory potency and added functionality enabling molecular probes. Their potential as Anticancer drugs was confirmed by blocking CD73 activity in tumor tissues in situ.

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