Improved tyrosine kinase inhibitor (TKI) selectively activates in tumor tissue, minimizing side effects in patients

A new strategy has been developed to reduce the often-serious side effects of tyrosine kinase inhibitors (TKIs), an important class of modern anticancer drugs. The novel drug is designed to restrict its activity with high selectivity to malignant tumor tissue.

The occurrence of severe side effects and the development of resistance are two of the biggest problems facing modern cancer therapy. Even the latest, highly targeted cancer drugs such as the tyrosine kinase inhibitors erlotinib (Tarceva) or sunitinib malate (Sutent) are affected by these problems, which can ultimately lead to the need to discontinue treatment.

The action of tyrosine kinase inhibitors is based on the specific inhibition of proteins overactivated in cancer cells, driving abnormal cell growth. However, clinical practice has shown that, as a result of the physiological functions of these proteins in healthy tissue, their inhibition can cause severe side effects. As a result, an acute need exists for strategies that more selectively restrict the effect of these highly promising new drugs to the malignant tumor.

This new strategy was developed by an interdisciplinary team of researchers from the University of Vienna and the Medical University of Vienna, both in Austria. The research team aimed to develop an inactive TKI that activates selectively in malignant tissue only, thereby preventing damage to healthy tissue and minimizing side effects in patients.

The new inhibitor leads to initial drug inactivation and, thus, has no activity under physiologic conditions. It is coordinated to cobalt(III), which releases the active drug only when it is reduced to cobalt(II) in the unusually low-oxygen conditions of tumor tissue. The tumor-selective effectiveness of this approach has been demonstrated both in living cells and in tumor-bearing organisms. The synthesis and testing of this inhibitor was described in Angewandte Chemie (2014; doi: 10.1002/anie.201403936).

So far no comparable strategy exists to reduce the severe side effects of tyrosine kinase inhibitors. It is hoped that this approach will eventually improve the tolerability of this type of therapy and allow these treatments to benefit patients who have previously had to discontinue it.

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