Epizyme & Celgene to Develop Epigenetics-Based Cancer Drugs
Apr26

Epizyme & Celgene to Develop Epigenetics-Based Cancer Drugs

Cambridge, Mass.-based Epizyme has scored $90 million upfront as part of a broad cancer drug development pact with Celgene. The deal adds to a spate of lucrative pacts to find compounds to modulate epigenetic targets, or enzymes that control gene expression without altering the underlying DNA. As we wrote in last week’s cover story, DNA carries the instructions for assembling all of life’s essential building blocks, but epigenetics dictates how and when that DNA is put to work. Recently, companies have made significant process in understanding the complex biology behind epigenetic processes, while also figuring out how to design compounds that can potently block epigenetic enzymes. With the science and business rationale for pursuing epigenetic targets dovetailing, big pharma and big biotech alike are forging deep ties with the handful of companies with expertise in the field. Under the three-year deal announced today, Celgene has the right to opt-in to the ex-U.S. rights for any unencumbered histone methyl transferase program at Epizyme. Eisai currently has the rights to Epizyme’s EZH2 inhibitor, while GlaxoSmithKline has a deep collaboration with Epizyme against undisclosed targets that would be excluded from today’s pact with Celgene. Epizyme says the partnership makes sense because Celgene shares “our vision in oncology and epigenetics,” says Epizyme’s president and CEO Robert J. Gould. “That’s been a fundamental bedrock of our partnering strategy--to partner with people who share our enthusiasm for this space.” Indeed, Celgene has long played in the epigenetics space, boasting two of the four currently marketed drugs that act on epigenetic targets. However, Celgene’s drugs, Istadax and Vidaza, hit first-generation epigenetic targets. Epizyme’s activities, meanwhile, center on one of the next waves of epigenetic targets: a family of enzymes called histone methyltransferases (HMTs). Of the 96 members of that family, Epizyme has identified roughly 20 HMTs for which there is a clear link to a specific form of cancer, Gould says.  To date, the company has two compounds—the EZH2 inhibitor partnered with Eisai, and a DOT1L inhibitor—in preclinical studies. (Check out last week’s cover story on epigenetics for more on how Epizyme went about discovering those two compounds.) Celgene is kicking off the pact by opting into the inhibitor of DOT1L, an HMT that is implicated in mixed lineage leukemia, a rare subtype of the blood cancer that the Leukemia and Lymphoma Society says affects about 1,500 new patients in the U.S. each year. With each program thereafter that Celgene buys into, Epizyme could score up to $160 million in milestone payments. The cash influx, coupled with the U.S. rights to the programs, “positions us nicely to maintain our independence, but also control our own future as a...

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Inching Toward An Obesity Drug Target?
Apr12

Inching Toward An Obesity Drug Target?

As the race to discover a new obesity drug continues, it's important to consider what makes a good obesity drug target. Before you bother putting a team of medicinal chemists on the job of making a small molecule that could be the next big diet pill, what do you need to know about the target you're chasing? A new paper in Nature (DOI: 10.1038/nature08921) raises that question this week. A research team led by Jijie Chai of the National Institute of Biological Sciences and Tsinghua University, both in China, has determined the molecular structure of FTO (fat mass and obesity-associated protein). This protein, as the name suggests, has been strongly linked to obesity. Before this paper, scientists knew what kind of protein FTO was- an enzyme that removes methyl groups from DNA and RNA, that prefers to clip methyls away from single stranded substrates. But they didn't have the molecular specifics. Now, with the structure solved, it paves the way for development of small molecules that can block or otherwise alter FTO's activity. But don't assume we've now got an easy path to new obesity drugs. There's more to the story. I touched on some of it here. FTO isn’t ready to be declared a prime obesity drug target, cautions Claude Bouchard, who specializes in the genetics of obesity at the Pennington Biomedical Research Center, in Baton Rouge, La. Geneticists cannot rule out that the gene for FTO is a surrogate for or is working with a nearby gene to affect obesity risk, he says. The natural substrates for FTO remain to be identified, and it may be tough to design drugs that selectively block demethylation of obesity-relevant ones, he adds. FTO is strongly linked to obesity in several studies. However, the gene for FTO is very close to another gene called FTM, Bouchard says. "They are almost universally co-expressed in animal models- these genes move in tandem," he says. So it's not clear from genetic tests so far whether FTO is the culprit, and if it is, whether it's working alone. The picture gets more interesting when you find out what FTM does. It's involved in the biology of cilia, the little hairlike structures that protrude from the surfaces of some cells. What's fascinating about that is that at least one genetic disorder of cilia, Bardet-Biedl syndrome, is characterized by obesity, Bouchard says. So, what's going on? We may need more genetic tests to figure this out. Or we could still use small molecule inhibitors of FTO activity to probe whether turning it off is enough to stop obesity. It would've been nice for a story like this...

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Epigenetics In D.C.
Aug03

Epigenetics In D.C.

At the end of last week, I witnessed a few dozen scientists and regulators with expertise in a dizzying diversity of disciplines—among them toxicology, epidemiology, molecular biology, public health, toxicology, genetics, pharmacology, reproductive biology, and exposure biology—confront the likelihood that an emerging arena of science, called environmental epigenetics, might change plenty about how they understand the relationship between public health and environmental conditions ranging from exposures to specific chemicals to child abuse. The conference, held in the Keck Building in downtown Washington, D.C., had a long title: “Use of Emerging Science and Technologies to Explore Epigenetic Mechanisms Underlying the Developmental Basis of Disease.” It was one of several workshops organized by the National Academies at the request of the National Institute for Environmental Health Science (NIEHS). “The objective is to gain understanding of what research is most needed to inform public-health decision-makers about chemicals that cause epigenetic effects,” the organizers wrote in a brochure for the workshop. In his engaging overview of just what epigenetics is and where in the scientific landscape it came from, Richard Meehan, program leader of the Human Genetics Unit at the Medical Research Council in Scotland (and bleary eyed from what turned out to be something like 20 hours of travel involving 6 boarding passes) shared a widely used definition of epigenetics with the group: “Epigenetics is the study of heritable changes in gene function that occur without changes in sequence of nuclear DNA.” The details behind these changes in gene expression requires drilling deep into the bedrock of molecular biology, but the basic idea is that there are mechanisms by which the macromolecular home of genes, chromatin, becomes chemically modified in such ways that genes can get switched on or off. This has consequences. Switch off a tumor-suppressor gene this way, for example, and you might be set onto a course that has cancer along the way. At least that is one way researchers are thinking about things. It seems that for just about any environmental input that these and other researchers have looked for epigenetic effects, they have found such effects. Among the specific, measurable epigenetic changes are methylation of certain cytosine bases along the DNA of chromatin and methylations, acetylations and other chemical modifications of histone proteins that comprise reel-like nucleosomes in chromatin around which DNA winds. Everything from exposure to nickel and estrogenic compounds such as bisphenol A to child abuse and maternal care (as in a rat mom’s licking and grooming of her pups) appear to elicit epigenetic changes. Much harder to nail down is whether these changes are, in fact, biologically consequential. Among the take home messages was that characterizing...

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