Selective Inhibitors of Genotoxic Stress-Induced IKK/NF-κB Pathways for Cancer Therapy
Challenge: Many cancer therapies such as chemotherapeutics or irradiation induce cancer cell death through DNA damage and DNA double-strand break. In response to such genotoxic stress, cancer cells activate DNA damage response (DDR) mechanisms leading to nuclear factor kappa B (IKK/NF-κB) activation via the IKK/NF-κB pathway which promotes cell survival. Therefore, the IKK/NF-κB pathway represents an attractive drug target since it is responsible for chemotherapy resistance which is a major hurdle for therapies involving genotoxic stress. However, IKK and NF-κB do have very diverse functions and general inhibition leads to blocking of beneficial effects and hence severe side effects. Thus, there is a need to develop new classes of pathway tailored inhibitors, which interfere only with a stimulus-specific NF-κB activation, while leaving other modes of NF-κB activation intact.
To identify selective inhibitors of genotoxic stress induced NF-κB signaling, a panel of different screening assays was developed which allowed to differentiate between NF-κB activation due to DNA double-strand break or due to activation by cytokines such as TNF-a or IL-1b. In the first round, a larger small molecule library was screened and the resulting hits were further filtered according to drug-like properties. Two promising compounds were selected from that first screening round for further profiling. Both compounds show potent suppression of NF-κB signaling in several cell types. Furthermore, they do not affect cytokine signaling and apoptotic cell death is significantly increased in tested cell lines. In contrast to PARP inhibitors, which gained increasing attention in recent years as inhibitors of DNA damage repair, the compounds developed in this project block NF-κB activation in a cell type independent manner. In parallel, a medicinal chemistry campaign was initiated and the hits were expanded into lead series with lead-like properties. Further derivatization and optimization of promising lead series is ongoing. Thus, the lead series may be developed into potent compounds as add-on therapy for chemotherapy and irradiation therapy. In addition, the compounds may also have an interesting potential as stand-alone therapeutics in certain cancer types.
Available for licensing or collaboration
European patent application EP16198731.8 pending (priority: November 2016)
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Hinz, M.,Stilmann, M., Çöl Arslan, S., Khanna, K.K., Dittmar, G., and Scheidereit, C. (2010) A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation. Mol Cell40, 63-74.
Dr Michael Karle
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