Im Rahmen des ACS Publikationssymposiums - Biologische und Medizinische Chemie vom 6. bis 8. März 2023 in Bonn präsentierte Carolin S. Pikullik (Arbeitsgruppe Prof. Christa E. Müller) ihr Poster mit dem Titel: "Protein kinase inhibitor ceritimib blocks ectonucleotidase CD39 - a promising target for cancer immunotherapy". Die klare, gut strukturierte und sehr ansprechende Präsentation ihrer wissenschaftlichen Arbeit begeisterte die Teilnehmer und Besucher des Symposiums. Sie wählten ihr Poster für den Publikumspreis aus und würdigten damit ihre wissenschaftliche Arbeit. Herzlichen Glückwunsch an die junge Nachwuchswissenschaftlerin Carolin S. Pikullik!
Carolin S. Pikullik über ihr ProjeKt:
📌Accumulation of extracellular adenosine has emerged as a key mechanism of immune escape. Adenosine represents one of the strongest physiological immunosuppressive mediators, but also promotes tumor cell proliferation, metastasis and angiogenesis. Ectonucleotidases, which catalyze the hydrolysis of ATP to AMP (CD39) and further to adenosine (CD73), are upregulated on many cancer cells. Thus, these enzymes are considered as promising targets for the (immuno)therapy of cancer. However, small molecule CD39 inhibitors suitable for therapeutic applications are lacking. Since most kinase inhibitors used in cancer therapy target the (intracellular) binding site for the co-factor ATP on protein kinases, we figured that some of them might additionally interact with the (extracellular) ATP substrate binding site of CD39. Thus, we screened 50 approved ATP-competitive protein kinase inhibitors on human CD39. Ceritinib, an anaplastic lymphoma kinase (ALK) inhibitor, was discovered to additionally inhibit CD39 at a therapeutically relevant concentration. The drug displays a non-competitive, allosteric mechanism of inhibition (Ki = 11.0 µM). Furthermore, Ceritinib features high metabolic stability, optimized physicochemical properties and brain permeation and is therefore an ideal starting point to develop more potent and selective CD39 inhibitors. We currently optimize the ceritinib scaffold for CD39 inhibition and/or dual CD39/ALK inhibition.
