 Juan Carlos Lopez |
 Andy Marshall |
Haystack chat
Molecular glue degraders (MGDs) are currently having a bit of a moment. In the first half of 2025, the number of papers describing such compounds has doubled.
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2025 has also witnessed a whole raft of MGD startups publish research related to their programs:
| Startup (location) | Scientific founders (location) | 2025 paper |
|---|---|---|
| Ambagon Therapeutics (Eindhoven, The Netherlands) | Michelle Arkin (UCSF, San Francisco, CA), Luc Brunsveld and Christian Ottman (Eindhoven University of Technology) | Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity |
| Cyrus Therapeutics (Seoul, South Korea) | Keon Wook Kang (Seoul National University, Seoul, South Korea) | High cereblon expression in neuroendocrine cancer confers vulnerability to GSPT1 molecular glue degrader |
| Matchpoint Therapeutics (Cambridge, MA) | Nathanael Gray and Tinghu Zhang (Stanford University, Stanford, CA) and Edward Chouchani and Jianwei Che (Dana Farber, Boston, MA) | Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α |
| Monte Rosa Therapeutics (Boston, MA) | Rajesh Chopra and Ian Collins (The Institute of Cancer Research and Cancer Research UK); Nicolas Thomä (Friedrich Miescher Institute, Basel, Switzerland) | Structure-guided strategy for identifying human proteins predicted to be compatible with cereblon-based molecular glue degraders (see below for further details) |
| Oniria Therapeutics (Barcelona, Spain) | Héctor G. Palmer, Esther Riambau, Isabel Puig, Josep Tabernero, Xavier Barril, and Carles Galdeano (Vall d’Hebron Institute of Oncology, University of Barcelona and ICREA) | Cullin-RING ligase BioE3 reveals molecular-glue-induced neosubstrates and rewiring of the endogenous Cereblon ubiquitome |
| Proxygen (Vienna, Austria) | Georg Winter (CeMM Research Center for Molecular Medicine, Vienna, Austria) | Selective analysis of protein degradation by mass spectrometry enables degradome analysis and identification of direct protein substrates of molecular glues |
| Proteovant Therapeutics (King of Prussia, PA) | Shaomeng Wang (University of Michigan, MI) | Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy |
| Sartar Therapeutics (Helsinki, Finland) | Olli Kallioniemi and Harri Sihto (University of Helsinki, Finland) | Pharmacokinetic profile and in vivo anticancer efficacy of anagrelide administered subcutaneously in rodents |
| SEED Therapeutics (King of Prussia, PA) | Ning Zheng (University of Seattle, WA), Michele Pagano (New York University, NY) and Avram Hershko (Technion Institute of Technology, Haifa, Israel) | UM171 glue co-opts CRL3 RING E3 ligase substrate coreceptor KBTBD4 as well as HDAC1/2, resulting in degradation of CoREST corepressors |
| Shenandoah Therapeutics (South San Francisco, CA) | Jerry Crabtree and Nathanael Gray (Stanford University, Stanford, CA) | A bivalent molecular glue linking lysine acetyltransferases to redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6 |
| Zenith Therapeutics (Basel, Switzerland) | Daniel Nomura (UC Berkeley, CA); Nicolas Thomä (Friedrich Miescher Institute, Basel, Switzerland), and Martin Stahl (former Roche, LifeMine) | Putative molecular glue niclosamide acts via ubiquitin E3 ligase CRL4AMBRA1-mediated degradation of cyclin D1 following mitochondrial membrane depolarization |
On the commercial front, the march of startups receiving funding shows no sign of slowing down, with Trimtech Therapeutics and Booster Therapeutics raising substantive rounds. The first few months of the year have also seen the continuation of last year’s pharma MGD scramble to license programs from Triana Biomedicines and Neomorph, with deals based around molecular glues from Abbvie and Merck targeting Neomorph and Springworks, respectively.
In June, one of the flagship developers, Kymera Therapeutics, priced a $250.8 million follow-on offering (no mean feat in the present market) after announcing positive phase 1 safety data for KT-621, a novel MGD against STAT-6, and clinching a deal with Gilead Sciencesforanother small-molecule glue targeting cyclin-dependent kinase 2 (CDK2). All in all, we count 27 companies currently active in this preclinical space (Ambagon Therapeutics, Amphista Therapeutics, Booster Therapeutics, Captor Therapeutics, Cyrus Therapeutics, Degron Therapeutics, Dunad Therapeutics, F5 Therapeutics, Frontier Medicines, Lifemine Therapeutics, Magnet Biomedicine,Matchpoint Therapeutics, Montara Therapeutics, Monte Rosa Therapeutics, Neomorph, Oniria Therapeutics, Proxygen, Sartar Therapeutics, SEED Therapeutics, Shanghai Dage Biomedical Technology, Shenandoah Therapeutics, SK Biopharmaceuticals (Proteovant Therapeutics),Triana,Trimtech,Venquis Therapeutics, YDS Pharmatech, and Zenith Therapeutics). There are likely more.
Unlike their more recent cousins, the PROTACs (proteolysis targeting chimeras), MGDs have a long history. The archetypal MGD, thalidomide, was discovered back in the 1950s. From the late 1990s, a new generation of immunomodulatory imide drug (IMiD) derivatives of thalidomide were synthesized, culminating with the approvals of lenalidomide and pomalidomide for myeloma (which formed the basis for the Celgene (now BMS) franchise).
Unlike PROTACs, which use two ligands with a linker and tend to be rather unwieldy, MGDs are small, single compounds that induce conformational changes in E3 ubiquitin ligases and target proteins, reshaping both to enable binding. The vast majority of MGDs bind Cereblon (CRBN), leading to ubiquitination of the protein of interest and degradation in the 26S proteasome, although work is progressing to broaden MGD action to some of the other 600 or so E3 ubiquitin ligases (e.g., DCAF11,15 or 16, DDB1, SIAH, KEAP1, VHL, β-TrCP, Nedd1 and, just last week, TRIM21).
A key challenge in finding new MGDs has been a lack of understanding of the structural rules whereby MGDs turn their target proteins into CRBN ‘neosubstrates’, which has meant MGD ‘hit-finding’ is much more challenging, with fewer degrees of freedom than PROTACs.
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What drug hunters have established is that many protein targets of glues contain a β-hairpin structural motif known as the ‘G-loop’. When a MGD brings a target together with CRBN, one end of the MGD interacts with a binding pocket in the C-terminal domain of CRBN, while the other end protrudes from the pocket and interacts with the G-loop (part of the so-called ‘degron’) in the neosubstrate. But how many proteins possess the β-hairpin G-loop or whether the loop is strictly necessary for MGD action have remained open questions. A recent study by Monte Rosa Therapeutics’ scientists starts to tackle these issues, disclosing a large cadre of potential new substrates for CRBN, some of which depart from the canonical β-hairpin G-loop, radically expanding MGD target space.
To map the full range of proteins potentially recruitable by CRBN through MGDs, the team led by John Castle and Sharon Townson developed computational algorithms to search for β-hairpin G-loop motifs in protein structures from two databases: Protein Data Bank and AlphaFold2. This approach resulted in 1424 candidate proteins, some of which were experimentally validated in MGD assays. The list included previously known neosubstrates, but also new proteins such as NEK7—a protein of interest as an autoimmunity target.
The researchers then wondered if the full β-hairpin structure of the G-loop is required for CRBN recognition and rescreened the structure databases looking for a minimal, structurally defined helical G-loop motif. This resulted in the identification of 184 additional potential neosubstrates, including mTOR, a well-established therapeutic target for drugs like rapamycin and sirolimus. Crystallographic data showed that the binding of this helical G-loop to CRBN is similar to that of the canonical β-hairpin G-loops.
As these protein–protein interactions have been well characterized, the team then tried to identify an even wider set of potential neosubstrates, looking now for proteins with sequences that might result in surfaces with electrostatic properties similar to known CRBN interactors, independently of secondary structure and the existence of G-loops. Using surface-matching algorithms, they identified and validated VAV1 (another autoimmune disease target) as a CRBN neosubstrate, providing compelling evidence that G-loops are not strictly necessary for the action of MGDs.
These findings show that CRBN recruitment through MGDs can be driven by a broader set of structural features than previously thought. The identification of a large number of neosubstrates potentially opens up a whole new set of previously ‘undruggable’ targets to MGDs (>1,600 proteins from many target classes, according to the Monte Rosa team).
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The big questions, though, are still ahead. How will drug developers mitigate the risks of ‘off-tissue’ toxicity as this swathe of novel MGD compounds and new targets make their way into the clinic?One answer to the toxicity concern is molecular glue antibody conjugates (MACs), which can better localize glues to the tissue of interest. But that’s a subject for a whole other future Haystack Chat!
Eric Sandberg
Next Phase Newsletter 