Stanford researchers create drug that flips driver of cancer into tumor killer

Stanford scientists have hatched a new type of drug that can turn a cancer promoter into a cancer killer.

In a study published in Nature Wednesday, researchers led by Stanford biochemists Nathanael Gray and Jerry Crabtree detailed how they developed a drug that can flip a protein that typically promotes the growth of B cell lymphoma into a protein that causes cancer cells to die.

The drug acts like a chemical harness, changing how an important B cell control gene is regulated by pulling in another protein that changes the first protein’s effect on gene expression.

Crabtree and Gray recently founded a new biotech company called Shenandoah Therapeutics, named after where Crabtree grew up, to help turn the research into new treatments. So far, the work is in its earliest stages — the drug has been tested in cells and mice, but not humans.

The scientists call the concept a TCIP — which stands for transcriptional/epigenetic chemical inducers of proximity. It’s analogous to another class of drugs in development, protein degraders or PROTACs. Those drugs have been likened to dumbbells: The target protein is on one end and the destructive enzyme is on the other, brought together by the drug in the middle. In this case, the drug in the middle brings together two transcription factors that change how a gene is expressed.

“It’s like a matchmaking service; you just need to get a little bit of proximity,” Gray said.

Nathanael Gray

Crabtree conceived the idea of targeting transcription and consulted Gray about it when Gray moved to Stanford from Harvard two years ago. Initially, Crabtree wanted to screen small molecular glues for potential candidates — following one of Lipinski’s rules, a concept in the development of pill-form drugs that says smaller molecules work better.

But Gray instead convinced him that they could design larger, two-headed molecules to bring the proteins together.

“People have this notion that it’s OK for Mother Nature to break Lipinski’s rules because it’s evolution and it’s a special molecule,” Gray said. “But when chemists do it with synthetic compounds, then you get in trouble.

“I think the jury’s still out about that,” he added.

Transcribing death genes

In the study, the researchers devised a drug candidate they call TCIP1, which binds to BCL6, a transcription factor that is deregulated in diffuse large B cell lymphoma. BCL6 usually helps keep normal B cells alive by stopping the transcription of cell death genes. But in lymphoma, that ability is leveraged to keep the cancer cells alive.

TCIP1 brings in another protein — BRD4 — to help activate the transcription of the cell death genes. “You’re creating a new chimeric transcription factor — that’s this unholy union between the BRD4 and BCL6,” Gray said.

Not only did TCIP1 help recruit BRD4, it also blocked BCL6 from recruiting other transcription repressors. That way, the activation from BRD4 won out, and the cell death genes were transcribed, causing the lymphoma cells to die.

Scientists have attempted to create medicines that block BCL6, but it’s difficult to completely inhibit every BCL6 protein. TCIP1 uses a “gain-of-function” approach, working with BCL6 instead of needing a full blockade. That means it can be potent without requiring very high doses.

“This might be helpful for treating large and poorly vascularized tumors in which it is difficult to achieve high drug concentrations,” NIH lymphoma researchers James Phelan and Louis Staudt wrote in a corresponding article in Nature.

“Overall, the development of TCIPs will be limited only by the imagination of cancer biologists and the innovation of chemists,” Phelan and Staudt wrote. “Such efforts promise to end the perception that cancer-promoting transcription factors cannot be targeted by drugs.”

Shenandoah Therapeutics, Gray and Crabtree’s biotech, will have to gather funding to push the science forward. Both Gray and Crabtree have founded biotechs before — Crabtree is a founder of Foghorn Therapeutics, while Gray has founded C4, Syros and Matchpoint Therapeutics. Shenandoah Therapeutics’ acting CEO is Isabella Graef, who is a co-founder of Eidos Therapeutics (and is also Crabtree’s wife).

But Gray noted that with the biotech markets down, it is harder to raise money for new ideas, though he believes they will get the funding they need for Shenandoah.

“The funds had raised a lot of money during the good times,” he said of the current environment. “But what they’re worried about is after they put in their initial money, who’s going to come in afterwards to get to the next value inflection point?”

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