Development and preclinical characterization of third-generation proteasome inhibitors

Automatisch geschlossen · 2013 bis 2015

Klinische Forschung
Monozentrisch am KSSG
Automatisch geschlossen

After validation of the proteasome as a prime target for innovative oncology drugs, the peptide borate bortezomib was approved as first in class proteasome inhibiting drug. Bortezomib provides reversible inhibition of the proteasomal beta 1 and beta 5 activities. Second generation proteasome inhibitors currently enter or undergo clinical development. They deliver irreversible target inhibition and oral availability and can
overcome bortezomib resistance in individual patients. However, the clinical
monoactivity of proteasome inhibition is still low (~40% in myeloma), resistance almost inevitably occurs, and solid tumors can still not effectively be attacked by proteasome inhibition. Inhibition of the beta 2 proteasome activity was recently identified to sensitize cells for beta 1/beta 5 inhibiting drugs, however, bortezomib and second generation proteasome inhibitors lack inhibition of beta 2 activity. In addition, proteasome inhibitors can not specifically be delivered to the target cells, and systemic toxicity, therefore, remains a problem. We aim here for a preclinical development and testing of compounds or drugs that reach beyond the properties of bortezomib and the 2nd generation proteasome inhibitors. These compounds either inhibit the beta 2 proteasome subunit (selectively or as pan-proteasome inhibition), and/or shall allow selective targeting of proteasome inhibitors towards the cells of interest. Regarding the first aim, we have co-developed the first beta 2 selective proteasome inhibitor available for preclinical testing, and have also identified the HIV drug nelfinavir as an oral drug with proteasome inhibiting activity, including beta 2 inhibition, in treated patients. Towards the development of targeted proteasome inhibitors, we shall make use of conjugates between novel proteasome inhibitors and innovative targeting devices (a a synthetic polymannose-protease-inhibitor conjugate, that we have co-developed
previously, and in addition a MHC II invariant chain antibody) that shall allow selective delivery of proteasome inhibitors into myeloma and acute myeloid leukemia cells. Together, this shall provide new perspectives to improve the clinical potential of proteasome inhibitors as targeted drugs not only against myeloma, but also AML and other malignancies.