For years, a protein inside our cells has quietly powered billions of dollars’ worth of cancer drugs. Now a team of researchers have discovered that this workhorse protein, called cereblon, in addition to its known functions, can also fine‑tune which proteins live and which are sent to the cellular trash.
The new study, published in Nature, is the first to identify and map an allosteric site — a hidden binding pocket — on cereblon. This research was led by Christina Woo, professor of chemistry and chemical biology, and her research group, in collaboration with a team of scientists at pharmaceutical company GSK and Scripps Research Institute.
Cereblon is part of a protein complex that tags other proteins for destruction. It became infamous because it was targeted by thalidomide, a drug prescribed for morning sickness in the 1950s and 1960s that caused birth defects. Decades later, thalidomide and related compounds were rehabilitated as treatments for blood cancers, precisely because they can redirect cereblon to tag disease‑causing proteins.
That principle is underpinned by a strategy called targeted protein degradation. Chemists design small molecules that bring bad proteins to cereblon, which then marks them for disposal by the cell’s disposal machinery.
Until now, nearly all of that work focused on cereblon’s orthosteric binding site — the same site thalidomide uses. The new study reveals that cereblon also has a second pocket, an allosteric site, that doesn’t replace the main binding site but changes what happens once it is engaged.
“This work is so novel that when I share it with audiences, you can see a ripple effect across the room of just how excited they are to learn about this new binding site on cereblon,” Woo said.
Scientists at GSK first identified a small molecule, SB‑405483, that appeared to boost certain signals, suggesting it might be binding somewhere else on cereblon.
“We immediately recognized that the discovery of an allosteric cereblon binder could represent a fundamentally new area of cereblon biology for exploration,” said Andrew Benowitz, executive director at GSK and former American Cancer Society postdoc at Harvard. “We knew of Professor Woo’s breakthrough contributions to the understanding of cereblon biology, and it seemed like a very natural idea to initiate a collaboration with her to better understand exactly what we had found.”
The Woo Lab led an extensive set of cell‑based studies, using reporter cell lines that produced different cereblon neosubstrates — proteins that can be targeted for degradation — fused to fluorescent tags. When a tagged protein was destroyed, its glow faded. By treating these cells with standard cereblon‑targeting drugs at the main site — with and without the new allosteric ligand — they could watch how the second site changed what was degraded.
In some combinations, the allosteric ligand made certain targets easier to destroy. In others, it protected them, reducing their degradation. In many cases, results depended on the existing cereblon‑binding drug with which it was paired.
“We saw that this small molecule can enhance the degradation of certain neosubstrates in the presence of certain orthosteric ligands, but also that modulating this allosteric site can inhibit neosubstrate degradation,” said first author Vanessa Dippon, a graduate student at the Kenneth C. Griffin Graduate School of Arts and Sciences. “It just completely changed the repertoire and landscape of cereblon neosubstrate degradation.”
For Woo, that selectivity is the heart of the discovery.
“The most immediate application is the potential to enhance efficacy of orthosteric ligands for the desired target, and reduce off‑target toxicity, by reducing the ability to recruit undesirable targets,” she said.
To understand why a hidden site could have such wide‑ranging effects, the team turned to structural biology. Working with cryo‑electron microscopy expert Gabriel Lander at Scripps, they obtained high‑resolution snapshots of cereblon in different shapes.
Those structures revealed that when both the main and the allosteric sites are occupied, cereblon moves through a previously unseen intermediate form and settles into a more closed shape that is especially good at grabbing proteins marked for destruction. They also showed that the allosteric ligand nudges the main‑site drugs into slightly different positions, offering a structural explanation for the shifting degradation patterns seen in cells.
The discovery opens several new possibilities. One is to use allosteric ligands as add‑on modulators for existing cereblon‑based cancer drugs — boosting their action on desired targets while limiting the degradation of proteins linked to side effects. Another is to design new molecular glues or two‑headed degrader molecules that use the allosteric pocket itself.
More broadly, Woo sees the work as a window into how cells may naturally regulate cereblon and related enzymes.
“It implies that there’s so much more to understand about the way that these E3 ligases are regulated in us,” she said. “That likely implies that there are small molecules — endogenous molecules — that are doing those functions already. And we’re just kind of catching up to understanding it.”
The project was partially supported by the National Science Foundation and the National Institutes of Health.
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