Accent Therapeutics launches to target the epitranscriptomic RNA code in cancer

Ten years ago, Robert A. Copeland left his job as vice president of cancer biology at GlaxoSmithKline to help start a company based on the emerging field of epigenetics—the study of how chemical modifications to DNA and its associated packaging proteins turn genes on or off. That company, Epizyme, is now developing compounds that target dysregulated epigenetic processes in cancer.

Last summer, Copeland left Epizyme to cofound a new company based on the young field of epitranscriptomics, the study of chemical modifications to RNA, rather than DNA. The Cambridge, Mass.-based start-up, Accent Therapeutics, has now announced raising $40 million in series A funding from the Column Group, Atlas Venture and EcoR1 Capital.

Three classes of proteins—writers, readers, and erasers—are responsible for making, binding, and removing the chemical modifications of the epigenetic code. The epitranscriptomic code follows a similar pattern, with writers, readers, and erasers acting on RNA. Collectively, these actors are called RNA-modifying proteins, or RMPs.

Scientists have discovered over 60 different covalent chemical modifications that alter the function, stability, and structure of essentially every major class of human RNA. “Over the past five years it’s become clear that many of these modifications and the proteins involved in these modifications are implicated in distinct human cancers,” Copeland says.

Since September, Accent has whittled a large list of RMPs down to 20 cancer drug targets. The firm has already begun designing small-molecule inhibitors for four of those, all “writer” enzymes. “These are all completely novel and unprecedented targets,” Copeland says.

Accent isn’t naming its four protein targets, but the scientific literature provides some clues as to why the company thinks RMPs may be good cancer drug targets at all.

One of the most well-studied epitranscriptomic modifications is N6-Methyladenosine (m6A), in which a writer enzyme adds a methyl group to an adenosine base in RNA. The modification can have many effects, including shortening the RNA’s lifespan, blocking a protein that normally binds that adenosine, or creating a new binding site for a protein.

“If you have alterations to these pathways, then it is very easy to imagine how it could lead to disease,” Copeland says. Methylation can profoundly change how much protein is made from a messenger RNA molecule, the kind of RNA that cells translate into proteins. Those protein levels, in turn, change a cell’s physiology, behavior, and even identity—all of which can give rise to cancer.

Abnormal levels of m6A are implicated in acute myeloid leukemia and glioblastoma, cancers of the blood and brain. But it is not readily apparent whether increasing or decreasing the amount of m6A would provide a treatment. Somewhat confusingly, there is evidence that increasing and decreasing m6A levels in leukemia cancer cells may have similar effects.

Since Accent is developing small-molecule inhibitors of writer enzymes, its scientists could conceivably be attempting to decrease m6A levels by blocking the well-studied enzyme METTL3, which is responsible for making the m6A modification. In fact, scientists have found elevated levels of METTL3 in leukemia cells.

The field of epitranscriptomics is too nascent for investors to know if targeting RMPs can actually treat disease. Copeland’s former company, Epizyme, still doesn’t have an epigenetics-based drug approved for sale yet. Yet epigenetics, and now the related epitranscriptomics, remain promising fields for finding new drug targets and attracting new funding. In March, Foghorn Therapeutics launched with $50 million to target epigenetic proteins involved in chromatin dysregulation, and in September Rodin Therapeutics raised $27 million to tackle epigenetic targets in brain diseases.

Reference

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