During the Leibniz Conference on Bioactive Compounds, on April 9, 2025, the “Leibniz Drug of the Year 2025” has been awarded to Dr. Ibrahim Morgan, Dr. Robert Rennert, Dr. Tuvshinjargal Budragchaa und Prof. Dr. Ludger Wessjohann for their research findings on SelectAHRyl A, a promising drug development candidate for AHR-expressing cancers.
Selective and efficient targeting of cancer cells remains a major challenge in anticancer drug development. In this study, they identified and characterized SelectAHRyl A as a highly selective prodrug activated in certain cancer cells, especially in triple negative breast cancer (TNBC, not responding to three standard treatments) but also liver cancer, for instance. Through a series of biochemical and cell-based assays, the IPB researchers elucidated its mode of action, revealing activation via the aryl hydrocarbon receptor (AHR) pathway. AHR is a receptor that detects foreign substances (xenobiotics like drug molecules) and initiates their destruction in the cell, e.g. to make it resistant. Upon AHR-mediated metabolism, the benign SelectAHRyl A molecule though is not destroyed but is converted into SelectAHRyl B, a cytotoxic derivative that remains trapped within the cancer cell until it is dead. This self-selective auto-activation mechanism not only enhances tumor specificity but also minimizes off-target effects. Furthermore, SelectAHRyl B inhibits a family of enzymes crucial for the function of the cancer cell, rather than a single target, thereby reducing the likelihood of resistance development. In conclusion, the originally non-toxic SelectAHRyl-A hijacks a cancer cells drug defense mechanism, the AHR pathway, to turn itself into a multiply active toxin inside the cancer cell. These findings position SelectAHRyl A as a promising “first in class” drug development candidate for AHR-expressing cancers.
