Mitochondrially targeted compounds and its clinical potentialAuthor(s): Jan Stursa
Mitochondria have been recently recognized as an emerging target for new anti-cancer drugs. It is one of the main organelles in the cells participating in many important biochemical processes, including oxidative phosphorylation, which is crucial for the cell as a part of ATP synthesis. Mitochondria are also responsible for apoptosis by triggering the complex cell death process. A frequent approach to mitochondrial targeting is tagging the biologically active agents with lipophilic cation such as the alkyl triphenylphosponium moiety. Delocalized hydrophobic cations readily accumulate across the mitochondrial membrane due to the highly negative potential on the matrix side of the membrane.
Here we will present novel mitochondrially targeted compounds developed by our team. An example is mitochondrially targeted tamoxifen (MitoTam), an inhibitor of complex I of the respiratory chain, which has recently entered Phase I clinical trial. We will present the biological properties of MitoTam including its synthesis from milligram amounts scaled up to kilogram amounts. The strategy of preclinical evaluation and its design needed for approval by the regulator prior to launching the Phase I clinical trial will also be discussed.
Apart from the anti-cancer properties, MitoTam and its derivatives also selectively kill senescent cells. Cellular senescence is stress response activated in damaged cells. Inability of immune system to eliminate these senescence cells leads to development of age-related diseases, tissue damage, inflammation and enhanced carcinogenesis. Therefore, we can talk here about the repurposing of MitoTam to another clinically relevant scenario.
Another field of our interest are mitochondrially targeted compounds with the ability to affect iron metabolism. Exemplified by deferoxamine derivatives, these agents feature a migrastatic and tumour suppressive properties. Synthesis and biological results of such compounds will be presented.