At the ACS Publikation Symposium - Biological and Medicinal Chemistry in Bonn, March 6-8, 2023 Carolin (working group Prof. Christa E. Müller) presented her poster entitled: "Protein kinase inhibitor ceritimib blocks ectonucleotidase CD39 - a promising target for cancer immunotherapy". The clear, well-structures, and very appealing presentation of her scientific work inspired the particpants and the vistors of the symposium.Together they selected their poster for the audience award. Congratulation to the young an aspiring scientist Carolin S. Pikullik!
Carolin S. Pikullik about her project:
📌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.
