Syros Takes On Super-Enhancers

At any given moment, in any given cell in your body, thousands of genes are expressed. Some might be barely turned on, eking out their protein, while others might be turned up to full volume. Scientists have long tried to understand how those dials are turned: How does a cell know when and how much of each protein needs to be made? And more important for drug development, how do the volumes differ in a diseased cell compared with a normal one?

In 2013, Richard A. (Rick) Young’s lab at Massachusetts Institute of Technology showed that of the 20,000 genes expressed at any given time, only a few hundred are going full blast. Moreover, these key nodes in the cellular network control both the fate of the cell—what makes it, say, a blood cell rather than a nerve cell—and the state of individual genes in the cell. Young dubbed these long sequences of cranked-up genes and the transcription factors that bind to them “super-enhancers.”

Imagine if you could develop a drug to disrupt those cellular hot spots. On the same day that Young and Harvard University’s James E. (Jay) Bradner published a paper in Cell unveiling super-enhancers linked to cancer, the two scientists cofounded Syros Pharmaceuticals to do just that. Since then, the Watertown, Mass.-based biotech firm has raised more than $80 million to develop small molecules to upend those regulators of gene control.

The company’s gene control approach departs from the current cancer drug discovery paradigm, where researchers often focus on a genetic mutation or faulty signaling pathway. Instead of filing through all of the mutations in a DNA sequence to figure out which ones are important drivers of disease, researchers can focus on the few hundred super-enhancers in a given cell that control the expression of critical genes, explains Nancy Simonian, the company’s chief executive.

She likes to think of a super-enhancer as “a functional readout of what is really important to the cell.” In other words, super-enhancers are like giant blinking arrows, pointing researchers to the few key genes in a cell that matter most. By following those arrows to the cluster of genes and transcription factors that dictate cellular activity, Syros hopes to unearth new drug targets.

The first step in Syros’s drug discovery effort is to find super-enhancers for a given cell type. The firm uses patient tissue samples to compare diseased cells and normal ones. Where they diverge, Syros researchers can then focus on the genes and transcription factors that make up or are controlled by that super-enhancer. The hope is that using a small molecule to dampen the activity of just one player in the node will upend the balance in the diseased cell enough to shut it down.

Syros has validated its technology against known drug targets. For example, an analysis of 50 breast tumor samples enabled the biotech firm to identify the critical estrogen receptor in people with ER-positive disease and to pick out the HER2 gene in people with HER2-positive breast cancer. Overall, the technology picked up five out of six targets for drugs in Phase III clinical studies or on the market to treat breast cancer, a result that “made us very confident we’re picking up validated biology,” Simonian says.

Moreover, Syros’s technology also hit upon completely novel targets, as well as targets that other scientists have broached with small molecules but that weren’t linked to breast cancer. The company also looked at 50 tissue samples from people with acute myeloid leukemia (AML), with similar results.

“We see lots of white space with just the work we’ve done in breast cancer and AML,” Simonian says. Looking for super-enhancers in those two diseases has already yielded more than 40 novel drug targets, she notes.

Outsiders who have assessed Syros are impressed by what they see. “What I really like about Syros’s approach is the simplicity and elegance of it: Define the critical cancer drivers first, then develop drugs to hit the right targets,” says Sally Church, a former senior executive in Novartis’s oncology unit who is now a consultant and editor of Biotech Strategy Blog.

By identifying the essential transcription factors necessary for tumor survival, “Syros is increasing its chances of success severalfold,” Church says. “This is no ‘let’s chuck the mud at the wall and see if it sticks’ approach.”

The first project on Syros’s docket is a covalent inhibitor of CDK7, one of a family of protein kinases involved in transcription and a component of super-enhancers. It is based on a tool compound—a molecule that is useful in research but isn’t a good drug—that came out of the labs of Harvard’s Nathanael S. Gray, Syros’s third founder. Like most kinase inhibitors, the molecule settles at the ATP binding site, but it also attaches to a cysteine residue outside the kinase domain, a feature that makes it highly selective for its target.

Gray showed in cell-line studies of his lab’s tool compound that you don’t have to completely knock down gene expression controlled by the super-enhancer. Rather, dampening one component of these hot spots appears to be enough to lower the levels of the transcription factors on which a diseased cell relies.

Syros has replicated that finding in patient-derived tumor models. “Just a small perturbation causes them to undergo rapid cell death, whereas normal cells aren’t affected,” Simonian explains.

Gray and MIT’s Young also found that blocking CDK7 downregulates Myc, a gene notorious among drug developers for both its ubiquity in cancer and its intractability. Myc’s perniciousness—it is mutated in up to 20% of cancers—has been known for 30 years, but drug developers have not been able to shut it down.

Syros licensed the intellectual property from Gray’s discovery and has since significantly advanced the properties of the tool compound. Syros isn’t disclosing when it will push its CDK7 inhibitor into human studies, but Simonian will say it isn’t looking for a big pharma partner for that program. “We have the cash, as well as the expertise, and an idea of how to get it into the clinic,” she says.

Although Syros’s initial work is in cancer, the biotech company has some preliminary data on using its technology to discover targets relevant to spinal muscular atrophy and polycystic kidney disease.

Syros already has a second program in early preclinical studies, and Simonian expects the firm to have multiple compounds in the clinic by 2018. Thus, despite a go-it-alone strategy for the CDK7 inhibitor, she isn’t ruling out a future relationship. “Given the broad nature of the platform,” Simonion says, “we really are interested in finding a strategic partner.”