Ph.D Project: Towards new inhibitors of protein kinases: analogues of sorafenib
Research group: Prof. Isabel Rozas
Email: diezcece@tcd.ie

The drug Sorafenib (Fig. 1) is used for the treatment of kidney and liver carcinomas. It is the first oral multi- kinase inhibitor that targets Serine/ Threonine and receptor Tyrosine kinases in both the tumour cell and the tumour vasculature. These kinases play a key role in the regulation of cellular proliferation and death. Sorafenib has a dual action to stop the growth of cancer cells: It induces tumour cell apoptosis by targeting the MAP Kinase pathway involving the Raf/Mek/Erk[1] kinases and it also inhibits tumour angiogenesis by targeting receptors such as VEGFR 2, 3 and PDGFR.

Figure 1 Sorafenib structure
Rozas’ group has developed a family of compounds that are potential DNA minor groove binders and some of these compounds can also induce apoptosis in several types of cancer cell lines. Considering the structural similarities between these compounds and Sorafenib, taking into account the ‘rational’ multi-target approach for the treatment of cancer, and as a consequence of the promising results previously obtained, we have prepared a number of analogues of Sorafenib.

During the synthesis of these molecules a novel simultaneous reduction of nitro and carbonyl groups was discovered. [2] Moreover, viability assays and specific kinases testing have been performed to assess their cytotoxicity and to evaluate their role as potential protein kinase inhibitors. A number of these novel compounds were found to inhibit different cell types in the low M range, similar to Sorafenib. Additionally they display inhibition of the several Serine/Threonine kinases.

We now plan to test their ability to induce apoptosis in a number of cancer cell lines. Computational docking studies are currently ongoing to analyse the binding interaction of the compounds with the different targets in order to rationalise our biological results and allow for improvements in the anticancer activity of future compounds.

References:
[ ]    S. M. Wilhem, L. Adnane, P. Newell, A. Villanueva, J.M. Llovet, M. Lynch, Mol. Cancer Ther.  2008, 7, 3129-3140.
[2]    E. Diez-Cecilia, B. Kelly, I. Rozas, Tet. Lett., 2011, 52, 6702-6704.