Dual- and multi-targeting epigenetic inhibitors for the treatment of aggressive and/or recurrent cancers.
Cancer is a multifactorial disease that involves both genomic and epigenomic alterations. DNA and histone proteins are continuously modified through the dynamic deposition and erasure of chemical modifications. These epigenetic marks are recognized by specific reading complexes that regulate the gene expression programs and enable cells to develop and consolidate their identity. Oncogenes and oncoproteins mis-use these epigenetic processes to transform cells which thereby acquire the tumorigenic phenotype. Resetting the aberrant functioning of chromatin-modifying and reading complexes is an anticancer strategy that holds great promise because it complements and supports other therapeutic approaches. Despite exciting advances in the field, the clinically successful drugs that interfere with epigenetic process are few. With this overarching objective, our project intends to deliver a portfolio of new dual- or multi-targeting epigenetic inhibitors that simultaneously hit two or more chromatin targets and exploit innovative pharmacological strategies. Since epi-targets often work synergistically to orchestrate gene expression programs, multi-targeting compounds can be particularly effective to acutely interfere with aberrant chromatin processes.
On this basis, our project is tackling the dysregulated methylome of aggressive and/or recurrent cancers with specific reference to melanoma, triple negative breast cancer, glioma, and acute leukemias. The targets of our project for inhibitor development will be ¿methyl writers¿ (DNA methyltransferases and lysine or arginine methyltransferases) and ¿methyl erasers¿ (lysine demethylases). The newly designed and synthesized chemical entities will be fully characterized by chemical, biochemical, and biophysical methods, and will be probed for their bio-pharmacological, cellular and molecular effects (target engagement, cell cycle, apoptosis, autophagy, necroptosis).