With a new approach, startup Flare Therapeutics may solve the transcription factor puzzle

Abbie Celniker once completed a 1,000-piece jigsaw puzzle that was solid white.

As a partner at Third Rock Ventures, a Massachusetts firm that identifies and funds new biotech companies, Celniker can analogize her jigsaw acumen to her latest startup, which she believes has found the missing piece. 

With a launch from stealth comes Flare Therapeutics, boosted by an $82 million series A financing round. The "secret sauce," as Celniker puts it, is a unique “switch site” approach to targeting transcription factors, which control gene expression and play a central role in cancer and other diseases. 

This is not gene therapy, where a drug made out of DNA corrects a missing gene. Flare is using the most common kind of drug, a pill, to deliver chemicals that bind to a TF protein.

For decades, scientists have known the central role of TFs in diseases. Despite this, fewer than 1% of TFs have been successfully targeted for therapeutics, because conventional rules for drug design do not apply to them.

“People have not had success finding small molecule therapies that control or regulate transcription factors,” said Celniker, who is Flare’s interim CEO. “They’re big, important drivers of disease, but they’ve been really hard to drug.”

So when Flare’s co-founder and chief scientific officer Rob Sims, a self-described “transcription factor nerd,” presented his idea to Third Rock, it was met with a few eye rolls. 

But Sims knew he was on to something. 

In April of 2019, he had come upon the findings of an Oxford crystallographer who detailed how a new medicine worked on TFs. Many such studies had been done, but, in most, the TFs were isolated. This study differed by looking at how TFs operated together and in differing metabolic states. The findings provided new understanding of how TF complexes associate and cooperatively interact to facilitate DNA recognition.

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Sims had sworn off TFs when he arrived at Third Rock as an entrepreneur-in-residence, but he kept coming back to the study, realizing that it provided a “framework for how to drug these proteins,” he said.  

Finally, Sims set up a confab with University of Oxford professor Fraydoon Rastinejad in February of last year, just before the start of COVID-19 travel restrictions.   

“It was just this incredible meeting where the momentum carried into the summer and into the fall and we started to wonder if this truly could be different and unique and finally crack this area,” Sims said. “And over the course for the remainder of the year, we continued to beat that idea up: Can this truly be a company?”

Rastinejad was a believer and signed on as a co-founder. Two other co-founders were convinced as well. University of Pennsylvania Professor Mitch Lazar and University of Texas Southwestern Professor Steven McKnight, who also co-founded TF companies Tularik and Peloton.

“Tularik 30 years ago was way ahead of its time,” Sims said. “The tools and things we can bring to bear on the problem, it’s just a different universe today. Now is the time.”    

From the seminal work of its co-founders, Flare has uncovered switch sites, druggable regions that are key targets for TF regulation to address mutations that cause disease. The finding has produced a pipeline of three precision oncology projects, the most developed of which is two to three years from the clinic, Celniker said.

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“We’re excited to finally take the wrapper off and tell the world about our approach,” Sims said. “There are hundreds of diseases that we know are caused by alterations of transcription factors. So, this is a drug discovery problem that has to be solved for patients. Our mission is to play a part in solving it.”

To sum the discovery up, Sims revisits the puzzle analogy.

“That one missing piece is like our switch site. You can see this one piece that can punch above its weight,” Sims said. “It creates the opportunity. You can now begin to frame the problem. Here is the bullseye. Now we know where to point our drug discovery machine. That’s what our switch site enables.”