Epigenetics as a paradigm for cancer treatment: chemically targeting the histone lysine methyltransferase EZH2

Published on December 31, 2015   21 min
0:00
The title of today's talk is 'Epigenetics as a Paradigm for Cancer Treatment: Chemically Targeting the Histone Lysine Methyltransferase EZH2. My name is Sharad Verma and I work for GlaxoSmithKline, and I support the Oncology Therapeutic area in the area of early development.
0:24
The objectives of today's presentation are as follows. I would like to provide the viewer with an improved understanding of first, cancer as an unmet medical need, and then discuss epigenetics as a paradigm for treating cancer. In this regard, I will discuss epigenetics from a structural mechanistic standpoint, and then focus on one particular class of enzymes called histone methyltransferases. I will then discuss EZH2 as an example within this target class. Specifically, what is EZH2 and what it does and the rationale for targeting EZH2 in oncology. Further discussion will then focus on the development of EZH2 inhibitors. First, some general drug discovery themes, and then discussion around some of the lead molecules that have arisen from those discovery efforts, and then finally a summary and future outlook.
1:33
Cancer is a major unmet medical need of global significance. It is the leading cause of death worldwide and the second leading cause of death in the United States, following coronary heart disease. It is estimated by the American Cancer Society that in 2015, there will be 1.66 million new cases of cancer diagnosed. The number of cancer cases is continually rising especially in the United States and European Union countries. This is in large part driven by an aging population, as cancer cases are more prominent in an elderly population. 2/3rds of all cases are in patients 65 and older.
2:22
In addition to surgery, radiation, and chemotherapy, targeted therapy has also been used prominently for the treatment in management of cancer over the last 15 years. In this regard, a number of highly potent and selective small molecule kinase inhibitors which are signaled transduction inhibitors have been introduced. Starting with Imatinib, or Gleevec, which was approved in 2001 for the treatment of CML, this ushered in an era of targeted therapies and a number of small molecules which are shown in this slide, have been used for the treatment of cancer. This does not show all of the small molecule kinase inhibitors that have been developed but this is a representation of many which have. These commonly target ATP as a cofactor.
3:17
In the next slide are some of the challenges that are listed that need to be considered. Despite the success with signaled transduction inhibitors, there is still much to do. One must consider that cancer consists of multiple diseases with multiple causative factors. There are network and pathway cross-talk, feedback inhibition loops, compensatory mechanisms, and mutations and translocations. All of these contribute to the conferrance of resistance. Advances in tumor biology are providing additional targets and mechanisms to explore. In this respect, epigenetics has been identified as one of the cutting edge areas for the next generation of targeted therapies. So in addition to signal transduction inhibitors, epigenetic inhibitors are also seen as a potential modality for the treatment of cancer.
4:19
In the next slide are some details around epigenetics from a structural standpoint. Epigenetics refers to heritable changes in phenotype or gene expression that don't involve a change in DNA sequence. And essentially, these are processes that act at the level of the chromatin to regulate gene expression. Epigenetic dysregulation is not limited to just cancer but it is implicated to diseases of inflammation and metabolic disorders.
4:53
In the next slide are some definitions of the key terms I will be alluding to throughout the rest of the talk. As mentioned, epigenetics refers to a stable heritable change in phenotype or gene expression in an organism or cell, resulting from changes in a chromosome that are not caused by a change in DNA sequence. The chromatin refers to DNA that is coiled around histone proteins and compacted into highly ordered structures in the nucleus. A histone is a type of basic protein that forms the unit around which DNA is coiled in the nucleosomes of eukaryotic chromosomes. The nucleosome is the basic unit of DNA packaging in eukaryotes consisting of segment of DNA wound in sequence around four histone protein cores. A histone methyl transferase is a class of enzymes that will add a methyl group onto the lysine or arginine tails of histone proteins. A post-translational modification is a chemical modification of a protein after its translation. S-Adenosylmethionine or SAM, as it's abbreviated, is a universal methyl group donor of all methyltransferase reactions. And so these are some of the key terms that are associated in the discussion around epigenetics.
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Epigenetics as a paradigm for cancer treatment: chemically targeting the histone lysine methyltransferase EZH2

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