A11: SFB 1328

A11 Project movie

A11: Summary

This project is aimed at developing potent, selective modulators of the ATP-hydrolyzing ecto-enzymes CD39 and NPP1. The extracellular domain of the human CD39, recombinantly expressed in Sf9 insect cells, will be co-crystallized with modulators that were developed in the first funding period. Structural information will allow further, targeted optimization of ortho- and allosteric modulators. Fluorophore-labeled modulators and photoactivatable prodrugs will be synthesized as biological tools. Selected modulators and labeled compounds will be synthesized in large scale to allow in vitro and in vivo studies by collaboration partners in models of inflammation and immunity.

Prof. Dr. Christa E. Müller

E-Mail: christa.mueller©uni-bonn.de
www: Pharmaceutical Institute & PharmaCenter Bonn, University of Bonn

Selected publications (*equal contribution)

Bi C, Schwermer F, Tang L, Müller CE, Liu W. Inhibitors of Ectonucleotidase CD39 for Immunotherapy of Cancer and Infections─Recent Developments and Future Perspectives. J Med Chem. 2026 May 4.
Bi C, Schwermer F, Schäkel L, Mirza S, Baburi H, Riziki P, Schmies CC, Winzer R, Idris R, Rolshoven G, Schilling J, Luckenbach L, Pelletier J, Brusoni LS, Al Hroub H, Al Hamwi G, Lopez V, Ahmadsay A, Raulien L, Sylvester K, Sévigny J, Tolosa E, Guse AH, Müller CE. Nucleotide-Derived Competitive Inhibitors of Ectonucleotidase CD39─A Promising Extracellular Target for Immunotherapy of Cancer. J Med Chem. 2026 May 1.
Winterberg KJ, Schwentner V, Gu F, Möckl F, Li G, Bauche A, Etzold S, Rosche A, Weiß M, Thuille N, Förster F, Woelk L, Werner R, Kovacevic D, Fehse B, Kurelic R, Nawrocki M, Huber S, Mittrücker HW, Meier C, Müller CE, Baier G, Skålhegg BS, de Deken X, Wahl-Schott C, Mair T, Siebels B, Cugota Canals R, Odoardi F, Lodygin D, Flügel A, Nikolaev VO, Diercks BP, Guse AH. Multiple signaling events are required for NAADP synthesis by DUOX2 and formation of Ca²⁺ microdomains to initiate T cell activation. Sci Signal. 2026 Jan 13;19(920):eadp4326.
Bi C, Mirza S, Baburi H, Schäkel L, Winzer R, Moschütz S, Keetz K, Lopez V, Pelletier J, Sévigny J, Schulze Zur Wiesch J, Claff T, Tolosa E, Namasivayam V, Sträter N, Müller CE. Synthesis, Characterization, Interactions, and Immunomodulatory Function of Ectonucleotidase CD39/CD73 Inhibitor 8-Butylthioadenosine 5'-Monophosphate. ACS Pharmacol Transl Sci. 2025 Apr 3;8(5):1401-1415.
Zhang H-J, Ociepa M, Nassir M, Zheng B, Lewicki SA, Salmaso V, Baburi H, Nagel J, Mirza S, Bueschbell B, Al-Hroub H, Perzanowska O, Lin Z, Schmidt MA, Eastgate MD, Jacobson KA, Müller CE, Kowalska J, Jemielity J, Baran PS. Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates. Nat Chem. 2024, 16(2):249-258.
Bi C, Schäkel L, Mirza S, Sylvester K, Pelletier J, Lee S-Y, Pillaiyar T, Sévigny J, Müller CE. Synthesis and structure-activity relationships of ticlopidine derivatives and analogs as inhibitors of ectonucleotidase CD39. Bioorg Chem. 2023, 135, 106460
Lopez V, Schuh HJM, Mirza S, Vaaßen VJ, Schmidt MS, Sylvester K, Idris RM, Renn C, Schäkel L, Pelletier J, Sévigny J, Naggi A, Scheffler B, Lee SY, Bendas G, Müller CE. Heparins are potent inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) - a promising target for the immunotherapy of cancer. Front Immunol. 2023 Aug 29;14:1173634.
Ahmadi P, Yan M, Bauche A, Smeets R, Müller CE, Koch-Nolte F, Haag F, Fliegert R, Kluwe L, Schulze Zur Wiesch J, Hartjen P. Human dental pulp cells modulate CD8⁺ T cell proliferation and efficiently degrade extracellular ATP to adenosine in vitro. Cell Immunol. 2022, 380, 104589.
Schäkel L, Mirza S, Winzer R, Lopez V, Idris R, Al-Hroub H, Pelletier J, Sévigny J, Tolosa E, Müller CE. Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 - a promising target for cancer immunotherapy. J Immunother Cancer 2022, 10, e004660.
Niemann B, Haufs-Brusberg S, Puetz L, Feickert M, Jaeckstein MY, Hoffmann A, Zurkovic J, Heine M, Trautmann EM, Müller CE, Tönjes A, Schlein C, Jafari A, Eltzschig HK, Gnad T, Blüher M, Krahmer N, Kovacs P, Heeren J, Pfeifer A. Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. Nature 2022, 609 (7926), 361-368.