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.
