Targeting Histone Methyltransferases for Cancer and Other Diseases
Drug discovery efforts targeting histone methyltransferases are intense and growing rapidly, partially because the clinical success with HDAC and DNA methyltransferase inhibitors provides validation for epigenetics targets in general and partially because the comparison to kinases is so compelling. There are now over 100 known methyltransferases (HMTs) that modify histones at specific Lys or Arg residues, and evidence for the role of mutated HMTs as drivers in tumorigenesis is rapidly accumulating. In this blog and over the course of the next few weeks, I’ll highlight recent papers and other sources of information on the therapeutic rationale for targeting HMTs as well as the methods and reagents used to identify selective inhibitors by high throughput screening.
At least half a dozen biotech companies are focused specifically on epigenetics. Epizyme and Constellation seem to have the most active HMT programs, and perusing their websites is a good way to glean information on targets and strategies. (Though not the focus of this blog, there is a good summary of some of the key pharma investments in epigenetics in this BioCentury Report from Jan, 2012.) Epizyme and their collaborators have been involved or directly responsible for much of the research underlying the therapeutic rationale for targeting HMTs, and their website is a treasure trove of very high quality information, including some of the key publications listed below. In addition, the non-profit, Structural Genomics Consortium is leading an epigenetics program that includes GSK, Lilly, Novartis and Pfizer and a number of university partners.
One of the foundational reviews on targeting HMTs for cancer is the 2009 review by Epizyme’s CSO, Robert Copeland, and his colleagues, in Nature Reviews Drug Discovery. And their more recent review, in Oncogene, ‘Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics’ tracks the progress that has been made in defining the role of specific HMTs, including Dot1L and EZH2, as drivers in tumorigenesis, and efforts to develop specific inhibitors for these and other HMTs.
Though most of the current efforts targeting HMTs is focused on cancer, they have been implicated in diverse diseases, and recent reviews describe what is known about their role in diabetes and atherosclerosis and inflammation, and cognitive impairments.
For more general information, the March, 2013 issue of Nature Structural Biology is an open access Focus on Epigenetic Dynamics, and, though not focused specifically on HMTs, there are very good reviews on overall histone modifications and on DNA methylation.
The validation of HMTs as therapeutic targets is very much in a nascent stage, but the potential is enormous. Highly selective HMT inhibitors have been identified and the first drug candidate, developed by Epizyme for DOT1L in MLL-rearranged leukemia, entered Phase I clinical trials in the fall of 2012; another Epizyme compound, for EZH2, is expected to advance into the clinic soon. With clinical validation, drug discovery programs targeting HMTs could easily become comparable to kinase programs over the next several years.
In the next blog, I will focus on the methods and challenges in detecting HMT enzyme activity and their impact on efforts to identify selective inhibitors.
