Prof. Claus Scheidereit, Max-Delbrück-Centrum für Molekulare Medizin; Dr Michael Willenbrock, Max-Delbrück-Centrum für Molekulare Medizin ; Dr Marc Nazaré, Leibniz-Forschungsinstitut für Molekulare Pharmakologie; Dr Peter Lindemann, Leibniz-Forschungsinstitut für Molekulare Pharmakologie
A major issue in treating cancer patients with chemotherapy or radiation therapy is the development of treatment resistance where cancer cells activate DNA damage response (DDR) mechanisms to circumvent apoptosis. In this context, the genotoxic stress-induced IKK/NF-κB pathway is highly relevant. As a key transcription factor, NF-κB activates anti-apoptotic genes and consequently, inhibition of DNA damage-induced IKK/NF-κB signaling promotes cancer cell death. Targeting pathways where DNA damage plays a significant role is a very promising approach in cancer research as the latest success stories of PARP inhibitors demonstrate. However, both IKK and NF-κB have very diverse functions and general inhibition leads to blocking beneficial effects. New selective inhibitors acting upstream from IKK/NF-κB interaction and leaving other modes of NF-κB activation intact have therefore a promising potential to treat chemotherapy or radiation therapy-resistant tumors.
A panel of different screening assays was developed to identify selective inhibitors of genotoxic stress-induced NF-κB signaling. This allowed differentiating between NF-κB activation due to DNA double-strand break or to activation by cytokines such as TNF-a or IL-1b. Screening of a larger small molecule library identified promising hits, which were further derivatized into lead series in a medicinal chemistry campaign - further optimization is ongoing. The leads show potent suppression of NF-κB signaling in several cell types and do not affect cytokine signaling. In-vitro testing proved that apoptotic cell death is significantly increased in genotoxic stressed cells. Moreover, in an intensive target search a promising new target was identified, which was so far not supposed to be related to this pathway. Further target validation is ongoing and the phenotype of a knock-out animal model indicates that the target is a suitable drug target. In addition to use as an add-on therapeutic, the compounds may also have an interesting potential as stand-alone treatment in cancers with DNA repair deficiency.
PCT patent application WO2018/087389 pending, priority of 14.11.2016