Syros Raises $53M More To Push Gene-Control Drugs Into Human Trials

The backers of Syros Pharmaceuticals are sparing no expense. The Watertown, MA-based biotech has reeled in a $53 million Series B round, a huge sum for a company based on relatively new understanding of fundamental human biology: the way our genes are controlled by extremely complicated signals within our cells.

“Our investors and board said to us that a disruptive breakthrough comes around infrequently, so we should make sure we’re investing appropriately to maximize the value,” said Syros CEO Nancy Simonian (pictured), whose company has grown to 25 employees since its emergence from stealth last year. Stacked on top of last year’s $30 million Series A round, the new financing was led by an anonymous Boston public investment firm and includes Polaris Partners, Aisling Capital, and Redmile Group. Flagship Ventures, Arch Venture Partners, WuXi PharmaTech Corporate Venture Fund, and Alexandria Venture Investments all returned to participate, as well. Flagship and Arch were the founding venture firms.

The cash should be enough to propel Syros’s lead drug candidate into human clinical trials, but Simonian declined to sketch out a timeline. Asked why so much money is necessary to push a drug program forward, Simonian said Syros will also expand “the platform and the product engine into multiple therapeutic areas.”

It’s rare for a cutting-edge startup to have such a long financial leash; for many biotechs with promising technology, once a lead program is identified, other programs are put on the back burner.

So what exactly is Syros up to? In a word, epigenetics—although it prefers not to use that term. (Syros prefers “gene control.”) Broadly speaking, the firm is developing drugs that make their way into the cell nucleus—a tumor cell, in the case of cancer—and disrupt the master switches that turn the cell’s genes on and off, especially the genes that are central to the cell’s state.

Syros’s work is made possible by new sequencing technology called ChIP-Seq, developed in part by Richard Young of the Massachusetts Institute of Technology’s Whitehead Institute in Cambridge, MA. Young is a co-founder of the company. The other two scientific co-founders are Nathaniel Gray of Harvard Medical School and the Dana-Farber Cancer Institute and Jay Bradner of Harvard Medical School, Dana-Farber, and the Broad Institute.

ChIP-Seq measures not just what genes are being turned on and off, but also the presence and activity of the molecular switches that are turning them on and off, and Syros is building maps of the complex, often tangled, circuitry. (Some of the switches turn on and off genes that create proteins that make other switches.)

Young and colleagues have dubbed the most important switches “super-enhancers” and estimate there are 200 to 300 per cell. Disrupt them, the hypothesis goes, and you kill the tumor cells that rely upon their regulation.

Syros is marrying ChIP-Seq with a lot of other techniques, including wet-lab work. It’s sequencing human tissue samples—some with disease, some healthy—to compare the genetic and epigenetic profiles, and ultimately figure out which super-enhancers are the culprits driving disease in certain patient populations. It’s done this most deeply in breast cancer and acute myeloid leukemia.

The firm’s lead drug candidate targets an enzyme called a transcriptional kinase. There are hundreds of kinases in the human body that, generally speaking, do the key work of changing the structure of other proteins. They are one of the most targeted classes of proteins in the drug world. Syros has zeroed in on CDK7, which is a component of some of the super-enhancers—and perhaps an Achilles’ heel. Block CDK7, and the drug might prevent the tumor cell from producing a protein it needs to survive.

Simonian won’t say which cancer the lead program will tackle first. One problem to overcome: CDK7 and other “CDK” kinases share similarities, so there’s a danger in hitting too many with the same drug. To that end, the firm is also doing medicinal chemistry work to refine some so-called “tool compounds”—usable for research but not to put into patients—that co-founder Gray developed to hit CDK7 specifically. “We have identified a number of cancers or cancer subsets that are highly dependent on CDK7 for their survival,” Simonian said.

For example, T-cell acute lymphoblastic leukemia is driven by problems with a gene called RUNX1. “RUNX1 had a large super-enhancer in front of it, and CDK7 was all over that super-enhancer,” said Simonian. Blocking CDK7, “these cells lose RUNX1 and undergo cell death.”

Simonian came to Syros after 10 years at Millennium Pharmaceuticals, where she ascended to chief medical officer. Millennium brought the multiple myeloma treatment bortezomib (Velcade) to market before it was bought by Takeda Pharmaceutical in 2008. Simonian is married to Flagship Ventures general partner Doug Cole, who helped found Syros and is on the board of directors. Cole was not involved in Simonian’s recruitment, she said—that task fell to Bob Nelsen of Arch Venture Partners and the founders—and “we have a conflict of interest management plan in place at the board level to deal with any issue[s] that arise,” she said.

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