Flare Therapeutics launches to target transcription factors

Flare Therapeutics has launched with $82 million in series A financing to discover small-molecule drugs that target transcription factors implicated in cancer. The life science venture capital firm Third Rock Ventures led the financing and pulled together the team of scientific cofounders on whose work Flare is based, including Fraydoon Rastinejad from the University of Oxford.

Transcription factors are responsible for regulating genes. A single one of these proteins can turn hundreds of genes on or off, so when transcription factors aren’t working properly, things can quickly go awry in a cell. Biologists have discovered a long list of transcription factors that are linked to cancer, sometimes due to mutations in the transcription factor itself, and other times because there is simply too much or too little of the factor in a cell.

Several commercial cancer drugs target a class of transcription factors called nuclear hormone receptors by activating, inhibiting, or modulating the activity of these receptors through their hormone binding pockets. But many other transcription factors linked to cancer have proven difficult to target because they lack obvious binding pockets.

In 2019, Rastinejad’s group published a study identifying a sensitive control switch that regulates a transcription factor called hypoxia-inducible factor-2 (HIF-2), which is overactive in some cancers but underactive in chronic kidney disease. Robert Sims, who joined Third Rock as an entrepreneur-in-residence in early 2019, was struck by the study and its implications for drugging transcription factors.

HIF-2 is formed when two different proteins, HIF-2α and ARNT, join together. Rastinejad’s team found two small molecules that bind a pocket in HIF-2α and either boost or diminish its ability to link up with ARNT and thus form HIF-2. Both molecules bind to the same pocket, but each displaces different amino acid residues in the pocket that act like separate levers for turning the transcription factor on or off (Nat. Chem. Biol. 2019, DOI: 10.1038/s41589-019-0234-5).

Sims was amazed that moving a single amino acid residue in the HIF-2α pocket could change the shape and function of the entire transcription factor and thereby turn hundreds of genes on or off. “I kept coming back to that paper,” he says. Sims also saw themes that went beyond HIF-2, and he wondered if similarly sensitive control switches could be found in other transcription factors.

In February 2020, right before the COVID-19 pandemic shut down research labs around the world, Sims flew to Oxford to meet Rastinejad and discuss transcription factor experiments that would form the basis of a new startup, now known as Flare. Along with Rastinejad and Sims, the company’s cofounders include Steven McKnight from the University of Texas, Southwestern and Mitch Lazar from the University of Pennsylvania. The Cambridge, Massachusetts-based startup is small—about a dozen people—and heavily relies on outsourcing many of its experiments.

Flare isn’t working on HIF-2 but is instead using Rastinejad’s HIF-2 study as inspiration for finding similar sensitive binding pockets—which Flare calls switch sites—in other transcription factors. Sometimes those switch sites are buried in a transcription factor; other times they will be formed by the interactions of complexes of two or more proteins. “It is not necessarily on the transcription factor,” says Abbie Celniker, a partner at Third Rock and Flare’s interim CEO.

The pharmaceutical industry’s tendency to develop drugs that target individual proteins, rather than protein complexes, could be one reason that so many transcription factors have been tough targets. Flare may have a leg up on previous research groups if its approach to looking for transcription factor switch sites pans out.

The potential is vast. Transcription factors are one of the most abundant classes of proteins, with more than 1,600 of them encoded in the human genome. Flare already has small-molecule discovery programs for three other transcription factors linked to cancer, plus early work on transcription factors linked to neurological, immunological, and genetic diseases.