Molecule Flips Switch on Gene Regulation

Designer drugs that switch the function of a transcriptional repressor into a gene activator could offer a new therapeutic strategy for combatting cancer cell growth.

A team led by Nathanael Gray, PhD, and Gerald Crabtree, MD, of Stanford University School of Medicine in California, developed the new class of two-pronged small-molecule therapeutics. Termed transcriptional/epigenetic chemical inducers of proximity, or TCIP, the drugs take the same dumbbell shape as proteolysis-targeting chimeras and other so-called hetero­bifunctional agents, grabbing onto different proteins with each of its arms.

But instead of targeting proteins for degradation, phosphorylation, or some other posttranslational modification, TCIPs tap into the transcriptional machinery to reprogram gene expression. They bring together a transcription factor that normally silences genes involved in cell death and an epigenetic regulator that broadly stimulates gene activity.

By linking these two proteins in just the right way, the gene-inhibiting function of the transcription factor is overridden by the gene-promoting action of the tethered partner. This happens at binding sites in the genome where the gene repressor normally acts. As a result, dozens of critical tumor suppressor genes that are otherwise kept in check get unleashed, leading to the destruction of cancer cells.

“This type of transcriptional recruitment is a major advance for the hetero­bifunctional space,” says Craig Crews, PhD, of Yale School of Medicine in New Haven, CT, who was not involved in the research.

As a proof of concept, the Stanford team showed that they could flip the function of BCL6, a protein that normally supports the proliferation of lymphoid neoplasms by suppressing genes involved in cell-cycle control. The researchers connected a small molecule that binds BCL6—and, in so doing, displaces corepressors of gene activity—with another that binds BRD4, a chromatin-remodeling protein that facilitates gene expression.

The resulting double-headed mole­cule, named TCIP1, boosted the activity of numerous proapoptotic genes. Some of these genes in turn reduced the expression of MYC and other oncogenic drivers. The collective rewiring of the transcriptional circuitry ultimately spurred the destruction of diffuse large B-cell lymphoma cells expressing high levels of BCL6. TCIP1 also proved tolerable, with no adverse toxicity issues in mice (Nature 2023 Jul 26 [Epub ahead of print]).

Gray, Crabtree, and their Stanford colleague Tinghu Zhang, PhD, launched Shenandoah Therapeutics to further advance the TCIP strategy. According to study authors, the team has also optimized TCIP1's design and, in unpublished experiments, shown that the drug has robust anticancer activity in a xenograft model of BCL6-dependent lymphoma.

Other drug compounds that inhibit or degrade BCL6 can have similar antitumor effects. But as Stanford's Andrey Krokhotin, PhD, points out, those types of therapeutics can only alleviate repression of BCL6 target genes.

“We do one more step,” says Krokhotin, a co–first author of the report. With TCIP1, “we not only inhibit BCL6, but we directly activate proapoptotic genes.” This gain-of-function mechanism sets the agent apart, he says, and allows for dosing at levels well below those necessary to induce cell killing with other drug types.

“The potency is extremely impressive,” says Will Gibson, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the research. “It leaves me optimistic that they have a shot of this working [in patients with cancer] without undue toxicity.”

Few binders currently exist for transcription factors besides BCL6, so the TCIP approach may be constrained by limited options for targets. But Crews is “bullish” that more binders will be found for this notoriously undruggable class of proteins. “There are so many new and emerging screening technologies that allow for ligand discovery,” he says. –Elie Dolgin

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