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Copeland R.A.,Epizyme
Nature Reviews Drug Discovery | Year: 2016

The drug-target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view drug-target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of target macromolecules that affect drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary drug-target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted. © 2016 Macmillan Publishers Limited.

Copeland R.A.,Epizyme
Future Medicinal Chemistry | Year: 2011

Although drug-target interactions are commonly illustrated in terms of structurally static binding and dissociation events, such descriptions are inadequate to explain the impact of conformational dynamics on these processes. For high-affinity interactions, both the association and dissociation of drug molecules to and from their targets are often controlled by conformational changes of the target. Conformational adaptation can greatly influence the residence time of a drug on its target (i.e., the lifetime of the binary drug-target complex); long residence time can lead to sustained pharmacology and may also mitigate off-target toxicity. In this perspective, the kinetics of drug-target association and dissociation reactions are explored, with particular emphasis on the impact of conformational adaptation on drug-target residence time. © 2011 Future Science Ltd.

Reversible histone acetylation on lysine residues, regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), plays an important role in the regulation of gene expression. Aberrant gene expression resulting from increased HDAC activity and histone hypoacetylation has been observed in human tumors and genetic knockdown studies support a role of HDACs in cancer. Treatment with small-molecule inhibitors of HDAC activity results in anti-tumor effects in a variety of transformed cell lines. Several HDAC inhibitors are in clinical development and show anti-tumor activity in cancer patients. Vorinostat (suberoylanilide hydroxamic acid) was the first HDAC inhibitor approved for the treatment of cancer and will be the focus of this article. © 2010 Future Medicine Ltd.

Copeland R.A.,Epizyme
Clinical Cancer Research | Year: 2013

The protein methyltransferases (PMT) constitute a large and important class of enzymes that catalyze sitespecific methylation of lysine or arginine residues on histones and other proteins. Site-specific histone methylation is a critical component of chromatin regulation of gene transcription-a pathway that is often genetically altered in human cancers. Oncogenic alterations (e.g., mutations, chromosomal translocations, and others) of PMTs, or of associated proteins, have been found to confer unique dependencies of cancer cells on the activity of specific PMTs. Examples of potent, selective small-molecule inhibitors of specific PMTs are reviewed that have been shown to kill cancers cells bearing such oncogenic alterations, while having minimal effect on proliferation of nonaltered cells. Selective inhibitors of the PMTs, DOT1L and EZH2, have entered phase I clinical studies and additional examples of selective PMT inhibitors are likely to enter the clinic soon. The current state of efforts toward clinical testing of selective PMT inhibitors as personalized cancer therapeutics is reviewed here. © 2013 American Association for Cancer Research.

Epizyme | Date: 2015-02-11

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.

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