{"id":2942,"date":"2026-03-19T15:30:45","date_gmt":"2026-03-19T15:30:45","guid":{"rendered":"https:\/\/americanvoiceofhealth.com\/index.php\/2026\/03\/19\/unlocking-hidden-pocket-on-a-billion-dollar-drug-target\/"},"modified":"2026-03-19T15:30:45","modified_gmt":"2026-03-19T15:30:45","slug":"unlocking-hidden-pocket-on-a-billion-dollar-drug-target","status":"publish","type":"post","link":"https:\/\/americanvoiceofhealth.com\/index.php\/2026\/03\/19\/unlocking-hidden-pocket-on-a-billion-dollar-drug-target\/","title":{"rendered":"Unlocking hidden pocket on a billion\u2011dollar drug target"},"content":{"rendered":"
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Christina Woo.<\/p>\n

Photos by Veasey Conway\/Harvard Staff Photographer<\/p>\n<\/figcaption><\/figure>\n

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\n\t\t\tHealth\t\t<\/a><\/p>\n

\n\t\tUnlocking hidden pocket on a billion\u2011dollar drug target\t<\/h1>\n

\n\t\t\tScientists identify path toward making cancer drugs safer and more selective\t\t<\/p>\n

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\n\t\tYahya Chaudhry\t<\/p>\n

\n\t\t\tHarvard Correspondent\t\t<\/p>\n<\/p><\/address>\n<\/p><\/div>\n

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\n\t\t\t5 min read\t\t<\/span>\n\t<\/div>\n<\/p><\/div>\n<\/header>\n

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For years, a protein inside our cells has quietly powered billions of dollars\u2019 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\u2011tune which proteins live and which are sent to the cellular trash.<\/p>\n

The new study<\/a>, published in Nature, is the first to identify and map an allosteric site \u2014 a hidden binding pocket \u2014 on cereblon. This research was led by Christina Woo<\/a>, 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.<\/p>\n

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\u2011causing proteins.<\/p>\n

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\u2019s disposal machinery.<\/p>\n

Until now, nearly all of that work focused on cereblon\u2019s orthosteric binding site \u2014 the same site thalidomide uses. The new study reveals that cereblon also has a second pocket, an allosteric site, that doesn\u2019t replace the main binding site but changes what happens once it is engaged.<\/p>\n

\u201cThis 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,\u201d Woo said.<\/p>\n

Scientists at GSK first identified a small molecule, SB\u2011405483, that appeared to boost certain signals, suggesting it might be binding somewhere else on cereblon.<\/p>\n

\u201cWe immediately recognized that the discovery of an allosteric cereblon binder could represent a fundamentally new area of cereblon biology for exploration,\u201d said Andrew Benowitz, executive director at GSK and former American Cancer Society postdoc at Harvard. \u201cWe knew of Professor Woo\u2019s 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.\u201d<\/p>\n

The Woo Lab led an extensive set of cell\u2011based studies, using reporter cell lines that produced different cereblon neosubstrates \u2014 proteins that can be targeted for degradation \u2014 fused to fluorescent tags. When a tagged protein was destroyed, its glow faded. By treating these cells with standard cereblon\u2011targeting drugs at the main site \u2014 with and without the new allosteric ligand \u2014 they could watch how the second site changed what was degraded.<\/p>\n

Vanessa Dippon. Graduate student Vanessa Dippon is seen in a portrait working at a hood in her lab in the Conant Chemistry Laboratory. Dippon helped uncover a hidden control dial on cereblon, a helper protein at the center of many blood cancer drugs. Veasey Conway\/Harvard Staff Photographer<\/figcaption><\/figure>\n

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\u2011binding drug with which it was paired.<\/p>\n

\u201cWe 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,\u201d said first author Vanessa Dippon, a graduate student at the Kenneth C. Griffin Graduate School of Arts and Sciences. \u201cIt just completely changed the repertoire and landscape of cereblon neosubstrate degradation.\u201d<\/p>\n

For Woo, that selectivity is the heart of the discovery.<\/p>\n

\u201cThe most immediate application is the potential to enhance efficacy of orthosteric ligands for the desired target, and reduce off\u2011target toxicity, by reducing the ability to recruit undesirable targets,\u201d she said.<\/p>\n

To understand why a hidden site could have such wide\u2011ranging effects, the team turned to structural biology. Working with cryo\u2011electron microscopy expert Gabriel Lander at Scripps, they obtained high\u2011resolution snapshots of cereblon in different shapes.<\/p>\n

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\u2011site drugs into slightly different positions, offering a structural explanation for the shifting degradation patterns seen in cells.<\/p>\n

The discovery opens several new possibilities. One is to use allosteric ligands as add\u2011on modulators for existing cereblon\u2011based cancer drugs \u2014 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\u2011headed degrader molecules that use the allosteric pocket itself.<\/p>\n

More broadly, Woo sees the work as a window into how cells may naturally regulate cereblon and related enzymes.<\/p>\n

\u201cIt implies that there\u2019s so much more to understand about the way that these E3 ligases are regulated in us,\u201d she said. \u201cThat likely implies that there are small molecules \u2014 endogenous molecules \u2014 that are doing those functions already. And we\u2019re just kind of catching up to understanding it.\u201d<\/p>\n

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The project was partially supported by the National Science Foundation and the National Institutes of Health.<\/p>\n<\/div>\n\n","protected":false},"excerpt":{"rendered":"

Christina Woo. Photos by Veasey Conway\/Harvard Staff Photographer Health Unlocking hidden pocket on a billion\u2011dollar drug target Scientists identify path toward making cancer drugs safer and more selective Yahya Chaudhry Harvard Correspondent March 9, 2026 5 min read For years, a protein inside our cells has quietly powered billions of dollars\u2019 worth of cancer drugs. …<\/p>\n","protected":false},"author":1,"featured_media":2943,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"loftocean_post_primary_category":0,"loftocean_post_format_gallery":"","loftocean_post_format_gallery_ids":"","loftocean_post_format_gallery_urls":"","loftocean_post_format_video_id":0,"loftocean_post_format_video_url":"","loftocean_post_format_video_type":"","loftocean_post_format_video":"","loftocean_post_format_audio_type":"","loftocean_post_format_audio_url":"","loftocean_post_format_audio_id":0,"loftocean_post_format_audio":"","loftocean-featured-post":"","loftocean-like-count":0,"loftocean-view-count":97,"tinysalt_single_post_intro_label":"","tinysalt_single_post_intro_description":"","tinysalt_hide_post_featured_image":"","tinysalt_post_featured_media_position":"","tinysalt_single_site_header_source":"","tinysalt_single_custom_site_header":"0","tinysalt_single_custom_sticky_site_header":"0","tinysalt_single_custom_sticky_site_header_style":"sticky-scroll-up","tinysalt_single_site_footer_source":"","tinysalt_single_custom_site_footer":"0","footnotes":""},"categories":[37],"tags":[],"class_list":["post-2942","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-staying-healthy"],"_links":{"self":[{"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/posts\/2942","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/comments?post=2942"}],"version-history":[{"count":0,"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/posts\/2942\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/media\/2943"}],"wp:attachment":[{"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/media?parent=2942"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/categories?post=2942"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/americanvoiceofhealth.com\/index.php\/wp-json\/wp\/v2\/tags?post=2942"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}