Tyrosine kinase inhibitor prodrugs to reduce side effects and resistance development

Over 10,000 people in the European Union are daily diagnosed with cancer and around 5,000 die from this disease every day. While the cure rate at early stages of the disease is frequently quite promising, the often poor prognosis at the disseminated stage leads to an unacceptable high number of cancer deaths. The development of so called tyrosine kinase inhibitors (TKIs) has been a milestone in cancer research during the last decade and currently around 25 TKIs are clinically approved as anti- cancer drugs. However, the clinical practice revealed similar to conventional chemotherapeutics insufficient tumor selectivity, which frequently leads to severe side effects and in addition very fast resistance development. Thus, new strategies to overcome these limitations and to generate TKIs with reduced systemic toxicity and resistance development are urgently needed. Recently, we have successfully developed the first epidermal growth factor receptor (EGFR) inhibitor prodrug which is inactive under normal conditions and can selectively be activated in the oxygen- deficient (hypoxic) milieu of the tumor tissue. Thus, aim of this project is 1) the extension of this prodrug concept for reduction of adverse effects to other tyrosine kinase inhibitors and 2) to overcome resistance development by combination of these novel prodrugs. The used combination settings are based on (pre)clinical data which revealed a promising synergistic activity of EGFR inhibitors with other kinase inhibitors, however, with strongly enhanced toxicity. Therefore, in this project novel derivatives of clinically approved TKIs will be synthesized. After proof of maintenance of the kinase inhibitory activity, the best candidates will be selected for the prodrug synthesis. Finally, the hypoxic activation as well as anticancer activity against TKI-sensitive and-resistant cancer cell lines will be tested in different prodrug combination regimens. Taken together, this project will lead to the establishment of a prodrug library, which not only enables the reduction of adverse effects for a single kinase inhibitor, but also allows the combination of prodrugs to avoid resistance development. This promising strategy will hopefully significantly increase the tolerability and efficacy of TKIs in anticancer therapy by overcoming the two major limitations: adverse effects and resistance development.

Over 10,000 people in the European Union are daily diagnosed with cancer and around 5,000 die from this disease every day. While the cure rate at early stages of the disease is frequently quite promising, the often poor prognosis at the disseminated stage leads to an unacceptable high number of cancer deaths. The development of so called "tyrosine kinase inhibitors" (TKIs) has been a milestone in cancer research during the last decade and currently around 60 TKIs are clinically approved as anti-cancer drugs. However, the clinical practice revealed - similar to "conventional" chemotherapeutics - insufficient tumor selectivity, which frequently leads to severe side effects and in addition very fast resistance development. Interestingly, for this huge class of approved TKIs (and despite their frequently severe side effects) there are just a few approaches in literature to develop prodrug or drug delivery systems so far. Based on the knowledge collected in the course of this project, several new hypotheses were generated, which led to the design of a huge panel of diverse TKI prodrugs against several oncogenes. In more detail, in this project we distinctly extended the available strategies for several types of TKIs including EGFR (gefitinib/erlotinib/osimertinib analogues), ALK/c-MET (crizotinib analogue), FGFR (ponatinib analogues, nintedanib) and VEGFR (sunitinib). For most of these TKIs, so far no prodrug approaches have been reported in literature. Here, a broad set of prodrug/drug delivery strategies (e.g., cathepsin B-cleavable and hypoxia-activatable organic prodrug systems, nanoformulations, cobalt(III) and platinum(IV) prodrugs, etc) were employed. Moreover, in course of this project several TKIs were further investigated for their biological behaviour (and promising combination strategies) to understand better from which prodrug setting they can profit. Consequently, the respective publications from this project show the large potential, but also drawbacks of different strategies. For example, the stability of cobalt(III) complexes of erlotinib could be distinctly increased and the first analogues with ponatinib could be generated. Also liposomal nanoformulations were very promising in vivo, with strongly improved anticancer activity compared to free ponatinib. In contrast, in case of sunitinib, the attachment of self-immolative linkers to the oxindole did not generate stable prodrug systems. Taken together, important contributions to the field of prodrugs and drug delivery systems for the class of TKIs have been generated. This will help to develop further improved derivatives and prodrug design approaches in future studies.