Mutations and dysregulation of protein kinases play causal roles in many human diseases, making kinases an important target for the development of pharmacological inhibitors. However, protein kinases are amongst the largest enzyme families with more than 500 putative protein kinase genes. As a consequence, the identification of inhibitors specific for individual protein kinases represents a significant and still unsolved challenge. Our group recently introduced a new concept of designing protein kinase inhibitors from organometallic scaffolds. These organometallic compounds display defined """"""""natural product-like"""""""" shapes which has been demonstrated that it can lead to picomolar protein kinase inhibitors with excellent selectivities. In these organometallic compounds, the metal serves as a template for organizing the threedimensional structure of the small molecule, permitting a diversity of structural motifs and shapes that are complementary to the shape of enzyme active sites and are accessible through economic convergent synthesis. It is our goal to apply this powerful synthetic methodology to the development of inhibitors for kinases which are implicated as important therapeutic targets for the treatment of melanoma. Specifically, we are seeking inhibitors for the protein kinases BRAF, BRAFV600E, PI3Ka, and GSK-3|3. The rationale for selecting BRAF and PISKa is based on extensive biological data on their constitutive activation in melanoma cells both in cultured cell lines and in patients'lesions. GSK-Sp has emerged as an new therapeutic target in melanoma through direct pharmacological activation of p53. The inhibitors will be developed from a ruthenium-pyridocarbazole scaffold which, in preliminary results, yielded already nanomolar lead structures with promising selectivity profiles. Improved inhibitors for these kinases will be obtained by modifying the ligand sphere around the ruthenium and by functionalizing the pyridocarbazole moiety. To reach this goal we will use a combination of synthetic structure-activity relationships, combinatorial chemistry, and rational design. The synthetic approach is complemented by a structure-based design for BRAF, BRAFV600E, PISKa (Project 3) and GSK-3|3 (Project 4). First cocrystal structures of ruthenium inhibitors with PISKa and GSK-Sp have already been solved. We expect to obtain highly potent and selective ruthenium inhibitors for BRAF, BRAFV600E, PISKa, and GSK-3|3, which will be used for in vitro and in vivo studies in collaboration with the groups of M. Herlyn (Project 1) and D. Herlyn (Project 2).
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