Dr Robert Huber, Max Planck Institute of Biochemistry; Dr Uwe Koch, Lead Discovery Center GmbH; Dr Bert Klebl, Lead Discovery Center GmbH
Lead Discovery Center
The immunoproteasome (ß5i, LMP7, iPS) is considered to be a novel and innovative drug target. Increased immunoproteasome expression levels are related to several inflammatory and autoimmune diseases, e.g. inflammatory bowel disease, rheumatoid arthritis, neurodegenerative diseases and systemic lupus erythematosus. High immunoproteasome expression levels are also found in cells of hematopoietic origin including hematological tumors.
Known proteasome inhibitors in clinical practice, such as Bortezomib, Carfilzomib, Ixazomib, etc. are covalent binders and non-specific proteasome inhibitors. They do not differentiate between the constitutive and the immune proteasome (cPS and iPS, respectively). They are subnanomolar active against the proteasome. Potent inhibition of the constitutive proteasome leads to a severe lack of tolerability in vivo. Consequently, clinical utility of these inhibitors is limited to the treatment of hematological tumors, such as multiple myeloma.
Proteasome inhibitors with largely improved selectivity for iPS (without any activity on cPS) may therefore turn into better tolerated treatment options for autoimmune disorders and even cancers.
The aim of this project is to generate novel, non-peptide, non-covalent small-molecule inhibitors of iPS that meet the criteria of a lead structure with drug-like properties and in vivo activity in autoimmune/inflammation models and/orin leukemia models.
The clinical utility of Velcade® and other proteasome inhibitors under development is limited because of their lack of specificity, poor metabolic stability, and/or irreversible binding to the proteasome causing significant side effects such as diarrhea, nausea and peripheral neuropathy. These shortcomings are the limiting factor of use of these proteasome inhibitors in cancer therapy. In addition, these adverse side effects are even more relevant for potential non-cancer applications. We have generated novel iPS inhibitors addressing these shortcomings by implementing two major innovative features : 1, (sub)nanomolar, but non-covalent mode of inhibition and 2, superior selectivity for iPS over cPS. The amazing iPS-selectivity has been achieved by addressing a novel binding pocket in the active site of iPS, which has been identified from its X-ray structures.
Hit-to-Lead Phase, approaching rigorous animal efficacy testing.
No patent filed yet.
Alexander, T., Sarfert, R., Klotsche, J., Kühl, A. A., Rubbert-Roth, A., Lorenz, H. M., ... & Taddeo, A. (2015). The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Annals of the rheumatic diseases, annrheumdis-2014.
Basler, M., Mundt, S., & Groettrup, M. (2017). The immunoproteasome subunit LMP7 is required in the murine thymus for filling up a hole in the T cell repertoire. European journal of immunology.
Basler, M., Maurits, E., Bruin, G., Koerner, J., Overkleeft, H. S., & Groettrup, M. (2018). Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome. British journal of pharmacology, 175(1), 38-52.
Huber, E., Basler, M., Schwab, R., Heinemeyer, W., Kirk, C., Groettrup, M., & Groll, M. (2012). Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor Specificity. Cell, 148(4), 727-738. dx.doi.org/10.1016/j.cell.2011.12.030