Proteome-Wide Discovery of Molecular Glues Revolutionizes Cancer Research

In the evolving landscape of cancer research, universities worldwide are pioneering innovative approaches to tackle previously undruggable proteins. A groundbreaking method known as PRISM (Proteome-wide Recruitment and neo-Interactome Screening for Molecular glues) is at the forefront, enabling scientists to systematically discover molecular glues—small molecules that induce new protein-protein interactions to trigger the degradation of cancer-causing proteins. Developed by researchers at Imperial College London in collaboration with the Francis Crick Institute and AstraZeneca, this proteome-wide screening platform represents a shift from serendipitous discoveries to data-driven strategies, promising new therapeutic avenues for hard-to-treat cancers.

Molecular glues work by 'gluing' a target protein to an E3 ubiquitin ligase, marking the target for destruction by the cell's proteasome machinery. This targeted protein degradation (TPD) bypasses traditional inhibitors that merely block protein activity, instead eliminating the protein entirely. In cancer, where mutated or overexpressed proteins drive tumor growth, such as BET family proteins in leukemia or SMAD4 in pancreatic cancer, molecular glues offer precision not achievable with conventional drugs.

🧬 The PRISM Platform: A Proteome-Scale Revolution

At Imperial College London's Department of Chemistry, Professor Ed Tate and Dr. Janine Gray have developed PRISM, a high-throughput proteomic workflow that maps compound-induced protein-protein interactions across the entire proteome. By screening focused libraries of compounds derived from known ligands, PRISM identifies ternary complexes where a small molecule bridges a cancer target and an E3 ligase. This method has been highlighted in a new PhD project co-sponsored by AstraZeneca, set to start in October 2026, focusing on rewiring cancer targets like those in lung and pancreatic cancers.

The platform combines chemical biology with mass spectrometry-based proteomics, quantifying neo-interactomes—newly formed protein complexes induced by glues. Early applications have validated hits using biophysical assays and cellular models, with machine learning models trained on the data to predict glueable sites. This university-industry collaboration, funded by £11.2 million from EPSRC and AstraZeneca since 2023, exemplifies how higher education drives next-generation therapeutics.

Recent Breakthroughs from Global University Labs

Beyond Imperial, researchers at the Broad Institute of MIT and Harvard, Stanford University, and CeMM in Vienna have advanced proteome-wide strategies. In a April 2026 Nature Chemical Biology paper, Zhe Zhuang and colleagues from Stanford and Broad discovered charged molecular glues (c-Glues) using targeted covalent screening and proteome-wide mass spectrometry. These glues, like ZZ1 and ZZ2, selectively degrade BET proteins (BRD4, BRD3) via the YPEL5-CTLH ligase, with cryo-EM structures revealing electrostatic-driven ternary complexes. Potent in leukemia and Ewing sarcoma cells, this work highlights universities' role in undruggable target conquest.

In February 2026, Miquel Muñoz i Ordoño and Georg Winter at CeMM/AITHYRA screened 330,000 compounds in leukemia cells, identifying dHTC1—a glue that binds ENL (Eleven-nineteen leukemia protein) and recruits an ubiquitin ligase for degradation. Published in Nature Chemical Biology, this functional cell-based screen disrupted ENL-dependent gene programs, halting leukemia growth. Such systematic approaches from academic labs are accelerating glue discovery.

Overcoming Undruggable Cancer Proteins

Cancer proteins like transcription factors (e.g., ENL, BETs) or intrinsically disordered proteins resist conventional drugs due to flat surfaces lacking pockets. Molecular glues remodel interfaces, enabling degradation. Harvard's Brian Liau lab demonstrated UM171 gluing HDAC to KBTBD4 for CoREST degradation in medulloblastoma, converging with cancer mutations that mimic glue effects. These insights from university structural biology are guiding rational glue design.

Statistics underscore urgency: ~80% of human proteome is undruggable by orthosteric inhibitors, per Broad Institute estimates. Proteome-wide screens address this, identifying glues for diverse E3 ligases like CTLH, expanding TPD beyond CRBN.

University-Industry Synergies Fueling Progress

Higher education is central to these advances. Imperial's EPSRC CDT in Chemical Biology trains PhD students in PRISM, linking academia to AstraZeneca's translational pipeline. Similar partnerships at Broad/Harvard with biotech firms validate hits in patient-derived models. Funding from EPSRC, NIH, and EU Horizon supports proteome infrastructure, with machine learning from datasets predicting glue hotspots.

Challenges remain: glue specificity, oral bioavailability, and resistance. Universities tackle these via multi-omics integration—proteomics with cryo-EM and AI—yielding structure-activity relationships for optimization.

Implications for Cancer Therapy and Patient Outcomes

Molecular glues promise smaller, brain-penetrant drugs for solid tumors. BET degraders show efficacy in MYC-driven cancers; ENL glues target AML. Clinical pipelines include CC-90009 (CRBN glue) in trials. Proteome-wide discovery scales this, potentially halving development timelines versus traditional screens.

• Selective degradation minimizes off-targets.
• Prodrug activation (e.g., ZZ1 sulfinic acid) enhances tumor specificity.
• Event-driven pharmacology overcomes steady-state inhibitors.

Real-world impact: In leukemia models, ENL glues reduced proliferation 50-70%; BET glues sensitized resistant lines.

Career Opportunities in Molecular Glue Research

Universities seek experts in chemical proteomics, structural biology, and computational chemistry. Imperial's PhD (stipend £31,805) exemplifies roles blending discovery and translation. Global demand surges for postdocs in TPD, with labs at Stanford, Broad, CeMM hiring.CeMM's ENL paper highlights interdisciplinary teams.

Future Outlook: Scaling Proteome-Wide Glue Discovery

AI-driven prediction from PRISM data will design glues de novo. Expanded E3 ligase space via CTLH unlocks 20% more targets. Universities lead clinical translation, with first glues entering trials 2027-2028. This era positions higher education as oncology innovation hubs, offering actionable insights for researchers pursuing TPD careers.

Explore university openings in chemical biology and oncology for hands-on proteome screening roles.

Photo by Jona on Unsplash