12:00 AM
May 15, 2014
 |  BC Innovations  |  Cover Story

Chromatin's rising tide

To capitalize on the full range of possible chromatin targets in and beyond oncology, industry and academia will need to delve deeper into how chromatin regulation is altered in disease, create tools that can reliably validate new targets and develop biomarkers that can improve the chances of success in clinical trials.

A wave of compounds targeting chromatin regulators entered the clinic in 2013, enabled by a decade of progress in understanding how chromatin dysfunction drives cancer.1

The first DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors were approved to treat subtypes of lymphoma in 2004 and 2006, respectively. In the following decade, research linked genetic alterations in functionally diverse chromatin regulators to many additional types of cancer.

That fueled the discovery of a second generation of compounds against new targets to treat genetically defined cancers (see "Select clinical-stage compounds that target epigenetic regulators").

Development of this wave of compounds was aided by technical advances that allow chromatin to be biochemically characterized in detail. Despite the progress, there remains a huge opportunity in unexplored targets and much to discover about how chromatin-dependent cellular pathways are affected in different diseases.

Against this backdrop, SciBX organized a panel of thought leaders to discuss the possibilities and challenges in developing chromatin-targeted compounds and outline ways to accelerate the translation of this information into disease-modifying therapies.

The panel identified three areas of chromatin drug development that are most in need of innovation.

First, new chemical tools to functionally characterize chromatin will be critical to validate targets-including those currently deemed intractable. These tools will enable a deeper understanding of how mutations in chromatin regulators alter cell signaling pathways and cell fate.

Panel member Jim Audia, CSO at Constellation Pharmaceuticals Inc.,

said that the optimal way to generate new tool compounds would be through collaborations between industry and academia such as the Structural Genomics Consortium (SGC).

"We realize that, regardless of your company, the academic community from outside it is immense compared to the resources that you can muster from within," he said.

Second, identifying predictive biomarkers and developing new methods to measure target engagement in vivo will be needed to accelerate progress to the clinic. Information about how hitting chromatin targets provokes different cellular responses between individuals will help companies select appropriate patient populations.

Because little is known about how the cellular pathways involved in chromatin regulation differ cell by cell or tissue by tissue, that information will need to be integrated from multiple experimental approaches.

"The simplest readout, if you were to perform knockdowns or if you had an inhibitor, would just be to look at changes in gene expression," said Peter Tummino, who at the time of the panel was head of GlaxoSmithKline plc's Cancer Epigenetics Discovery Performance Unit (DPU). "But what we are finding is that it is entirely insufficient. You can look across a set of cell lines and there's no similarity, there is no common gene profile. And so the next step beyond that is to think about what are the changes in histone marks-which you might expect to change. You can perform transcription factor mapping, if possible. It's the integration of several different data sets that begins to lead toward an understanding of mechanism."

Tummino is now VP and global head of lead discovery at the Janssen unit of Johnson & Johnson.

Finally, the panel said that chromatin regulators should also be targeted outside of oncology. Human genetic studies and an increased understanding of how cell fate is determined in neurology and immunology suggest that these two fields are next in line.

"We're years behind the oncology field in terms of looking at target association in the CNS," said Ankit Mahadevia, venture partner at Atlas Venture and acting CBO of Rodin Therapeutics Inc. "We're not wanting for genetically implicated targets in terms of CNS applications. Really, it's a lack of chemical probes and high-fidelity assays. The field is just so nascent, and there are fewer people, both in academia and in pharma, working on these associations."

Audia, Tummino and Mahadevia participated in the panel discussion alongside Jesse Smith, executive director of biological sciences at Epizyme Inc.; Charles Roberts, an associate professor of pediatrics at Harvard Medical School and director of the research program in solid tumors at the Dana-Farber Cancer Institute; and Stuart Schreiber, director of the Center for the Science of Therapeutics at the Broad Institute of MIT and Harvard, director of chemical biology at the Broad Institute, a professor of chemistry and chemical biology at Harvard University and an investigator at the Howard Hughes Medical Institute.

The panel was part of the 2nd SciBX Summit on Innovation in Drug Discovery & Development and was produced with support from the following sponsors: Acetylon Pharmaceuticals Inc., Amgen Inc., AstraZeneca plc, Atlas Venture, Biogen Idec Inc., GlaxoSmithKline, Karus Therapeutics Ltd., Merck & Co. Inc., Novartis AG, RaNa Therapeutics Inc., Sanofi and Zenith Epigenetics Corp.

Rational advancement

The first DNMT and HDAC inhibitors were developed when knowledge of chromatin regulation was sparse at best. Indeed, compounds that inhibit these targets were shown to have anticancer properties. Only later were their mechanisms of action established.

Since then, advances in whole-genome analysis and in vitro enzymology have ramped up knowledge about new enzymes and regulatory pathways and laid the groundwork for rational drug design.

According to the SGC, the key to exploiting this knowledge is a concerted chemical biology effort to probe the function of chromatin regulatory complexes in disease states.2

An example of the shift from phenotypic screening to rational design is the progress made since Schreiber's work in the mid-1990s that identified the mechanism of action of trapoxin, a natural product with anticancer activity that alters cell morphology.

Schreiber's 1996 study published in Science showed that the compound inhibited a previously uncharacterized protein that became known as HDAC1.3 At about the same time, independent teams identified the first mammalian histone acetyltransferase (HAT).

Now there are at least 18 known HDACs in humans, and companies including Acetylon and Karus are designing selective HDAC inhibitors.

Hundreds of additional proteins modify or alter chromatin structure. According to the SGC, there are 64 protein methyltransferases, two distinct families of protein demethylases and a slew of structurally distinct protein domains that bind acetylated or methylated histones or can physically remodel chromatin structure.

Schreiber said that the activities of chromatin-regulating protein families can be viewed as a natural extension of the signal transduction cascades that have been seen as potential drug targets for years.

"In signal transduction there are kinases that put on a phosphate mark, there are SH2 domains that bind the mark and there are phosphatases that remove the mark. And in chromatin it's exactly the same story. I'm a little amused that we have obfuscated this connection by using new vocabulary to describe proteins that behave like kinases and phosphatases. We call kinases 'writers', phosphatases are now 'erasers' and SH2 domains are 'readers'."

Schreiber said that compounds that target chromatin-modifying proteins have commonly been referred...

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