Anales RANF

P.24 URIDINE- AND CYTIDINE-BASED ECTO -5 ฀ -NUCLEOTIDASE- INHIBITORS: A NOVEL CLASS OF HIGHLY ACTIVE AND SELECTIVE CD73-INHIBITORS C. Dobelmann, 1 C. Renn, 2 V. Namasivayam, 2 S. Jain, 3 R. Balasubramanian, 3 C. E. Müller, 2 K. A. Jacobson 3 and A. Junker 1,3 1 University of Muenster, North Rhein Westphalia, Germany; 2 University of Bonn, North Rhein Westphalia, Germany; 3 National Institutes of Health, Bethesda, Maryland, USA. In 2018 J. P. Allison and T. Honjo won the Nobel Prize in Medicine “for their discovery of cancer therapy by inhibition of negative immune regulation.” 1 Ecto -5 ฀ -nucleotidase (CD73), an enzyme which catalyzes the hydrolysis of extracellular AMP to adenosine, is a possible target for immunotherapy. Unfortunately, inhibition of CD73 often suffered either from low inhibitory activity 2 of the compounds or from degradation products, which can activate P1 receptors. 3 To overcome these issues, we developed and synthesized a novel uridine- and cytidine-based class of CD73 inhibitors. 4 Our inhibitors display inhibitory activities in the low nanomolar range and the most active compound 9h (and its degradation products) additionally shows selectivity over the P1, P2Y 6 and P2Y 14 receptors. 4 Fig. 1: Interactions of the CD73 inhibitor 9h with the active site of CD73. 4 1. Press release: The Nobel Prize in Physiology or Medicine 2018. NobelPrize.org. Nobel Media AB 2019. 2. Baqi, Y. et al. J. Med. Chem. 2010 , 53 , 2076 −2086. b) Ripphausen, P. et al. J. Med. Chem. 2012 , 55 , 6576 −6581. 3. Bhattarai, S. et al. J. Med. Chem. 2015 , 58 , 6248-6263. 4. Junker, A. ꝏ ; Renn, C. ꝏ ; Dobelmann, C . ꝏ et al. J. Med. Chem , 2019 , 62 , 3677-3695.