Viewpoint pubs.acs.org/acsmedchemlett
Epigenetic Medicinal Chemistry Robert A. Copeland* Epizyme, Inc., 400 Technology Square, Cambridge, Massachusetts 02139, United States ABSTRACT: The past decade has seen tremendous growth in our understanding of epigenetics and chromatin remodeling. Small, organic molecule modulators of a number of chromatin modifying proteins (CMPs) have been reported over this time frame and several of these have advanced to human clinical trials. In this Viewpoint, I summarize the current state of medicinal chemistry efforts focused on epigenetic targets and attempt to provide some insight into future directions on which the community may wish to focus. en years ago the field of epigenetics and chromatin modification was just beginning to emerge as an area of biology that might have human disease association and might therefore yield interesting new targets for therapeutic intervention by small molecule drugs. By 2005 only one drug, azacitidine (Vidaza), targeting a chromatin modifying protein (CMP) family, DNA methyltransferases, had been approved for treatment of a human disease, myelodysplastic syndrome. Not long after (October 6, 2006), the first, nonselective histone deacetylase (HDAC) inhibitor, vorinostat, was approved by the FDA for treatment of cutaneous T-cell lymphoma. Over the past decade, much greater effort has been put forth in understanding the pathobiology of chromatin modification as well as in the discovery and development of small molecule inhibitors of CMPs.1 This has led to an explosion of knowledge in the area, as exemplified by the outstanding papers within this current issue of ACS Medicinal Chemistry Letters. These efforts have also translated into the clinical testing of inhibitors for a range of CMP mechanisms, including isozyme-selective HDAC inhibitors, selective inhibitors of protein methyltransferases (PMTs), an inhibitor of the lysine demethylase LSD1, and several inhibitors of bromodomain acetyl-lysine reader proteins (Table 1). Thus, it is becoming increasingly clear that various CMP mechanisms are amenable to modulation by traditional medicinal chemistry efforts. These efforts have been greatly facilitated by a rich bounty of high-resolution crystal structures for hundreds of target-compound complexes, allowing for rationale, structure-informed lead optimization for many CMP targets.2 Also noteworthy is the diversity of chemical structures and mechanisms that have proved useful in targeting these proteins; a broad spectrum of pharmacophore structures and binding modalities have been identified and have yielded highly potent, selective, orally bioavailable tool compounds. The next few years will be very important for this field and will clarify the clinical utility of these novel modulators of CMPs, as data from the various phase 1 and phase 2 clinical trials begin to emerge. Beyond the current efforts described above, what might the future hold for medicinal chemistry targeting CMPs? I see three key themes that will be important as the field continues to mature. Medicinal Chemistry on a Broader Spectrum of CMPs. While great strides have been made over the past decade to
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drug a number of CMPs, there remains a large swath of CMPs for which no pharmacologically tractable modulators have been reported. Consider the PMT target class. A 2011 survey identified 96 putative PMTs encoded by the human genome.3 The PMTs have been one of the most heavily investigated classes of CMPs. Yet today there are tool compounds and clinical candidates reported for
