Probing Cancer Epigenomes for New Therapeutic Strategies

Regulation of gene expression via chromatin associated factors and alterations of the cellular epigenome are fundamental to most biological processes, and many disease mechanisms. We are taking a protein family approach to understand how chromatin regulatory proteins recognize specific histone tail sequences and their posttranslational modifications. Proteins such as histone methyltransferases, demethylases, acetyltransferase, bromodomains and chromodomains mediate nuclear signaling networks that regulate epigenetic cellular states and gene expression programs. Systematic structural and biochemical analyses of these protein families are revealing key features of selectivity and regulation among these factors, enabling structure-based development of potent, selective, cell-active small molecule inhibitors of individual epigenetic regulatory proteins. Such compounds – Chemical Probes – are valuable tools for understanding epigenetic signaling mechanisms in cells and can link pharmacological tar are highly complementary to genetic methods and more closely mimic strategies for therapeutic translation.
I will present our recent work on Chemical Probes for protein methyltransferases and their characterization in human cancer models. These studies include the targeting of “undruggable” oncogenic transcription factors via modulation of the methyltransferases on which they depend, and targeting the stem-like tumour initiating cell populations in colorectal cancer and glioblastoma.