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Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity
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Abstract
This Perspective explores molecular glues and bifunctional compounds-proximity-inducing compounds-and offers a framework to understand and exploit their similarity to hotspots, missense mutations, and posttranslational modifications (PTMs). This view is also shown to be relevant to intramolecular glues, where compounds induce contacts between distinct domains of the same protein. A historical perspective of these compounds is presented that shows the field has come full circle from molecular glues targeting native proteins, to bifunctionals targeting fusion proteins, and back to molecular glues and bifunctionals targeting native proteins. Modern screening methods and data analyses with pre-selected target proteins are shown to yield either cooperative molecular glues or bifunctional compounds that induce proximity, thereby enabling novel functional outcomes.
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“Taken together, our findings provide another example that the underlying principles of molecular glue mechanisms might be rooted in the partial mimicry of naturally occurring PPIs at preexisting sites of high PPI propensity, interactions that are further enhanced by a matching molecular glue1,10,11,50–54.”
From Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry (2026) · cites this paper as [1]
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“…glues: agents that indeed are multiple ligands but interact with their targets to generate synthetic biological complexes with the ability to induce degradation (vepdegestrant, a PROTAC) or stabilize macromolecular complexes (tacrolimus, a molecular glue) (Békés et al., 2022; Schreiber, 2024).”
Neo‐Cysteine Molecular Glues for Targeting Mutated SMAD4 Protein
Kumari, P., Oum, Y. H., Miller, E. J., Qui, M., Du, Y., Mou, H., Singh, R. K., Fu, H., & Mo, X. (2026) · Angewandte Chemie International Edition · doi:10.1002/anie.202512791 · Cited by 2
Yang, Y., Li, Y., Zhou, Z., Li, H. L., Ma, Y., Bi, W., Li, M., Liu, X., Jia, Q., Han, L., et al. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.121374 · Cited by 1
Exploration of protein degradability enables fully endogenous MrTAC degraders
Seabrook, L. J., Karaj, E., Sindi, S. H., Brodie, G., Livelo, C. R., Franco, C. N., Campos, M., Leonard, J. T., Gao, F., Skowronska‐Krawczyk, D., et al. (2026) · Chem · doi:10.1016/j.chempr.2026.102998 · Cited by 1
Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design
Chae, S. J., DeBonis, J., Quinlan, J., Richards, R., Wang, J., Gutierrez, G. J., Tart, J., Couturier, M., Cuesta, S. M., Jin, M., et al. (2026) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c03125 · Cited by 1
“2,3 To understand how kinetic and thermodynamic parameters affect these diverse MG dynamics, we need a universal framework that comprehensively covers all MG mechanisms.”
Al-Karmalawy, A. A., Attia, M. I., Yousef, T. A., Al-Qazzan, M. B., Al-Akeedi, M., Khatib, A. O. A., & Hawas, S. S. (2026) · Archiv der Pharmazie · doi:10.1002/ardp.70261 · Cited by 1
“The ability of covalent glues to combine chemical perma-nence with biological selectivity offers notable pharmacological advantages [66].”
The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue
Hinshaw, S. M., Yuan, L., Noman, M. A. A., Martinez, M. J., Colombo, G. M., Dwyer, B. G., Ji, W., Romero, B. A., Forrest, I., Lu, J., et al. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.04.016 · Cited by 2
Al-Karmalawy, A. A., Sippl, W., Al-Dakhil, A., Yousef, T. A., Khatib, A. O. A., & Hawas, S. S. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110065 · Cited by 1
Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1–HSPA9 complex
Hayward, R. E., Berkeley, R. F., Gao, Z., Garhammer, M., Morizono, M. A., Njomen, E., Li, H., DeMeester, K. E., Cociorva, V., Herzik, M. A., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-026-02348-1 · Cited by 5
Design and Synthesis of 7-(N-Aryl Pyrrolidinyl) Indoles as Potential DCAF15 Binders
Devarajappa, R., Kiyeleko, S., Hocine, S., Cosson, V., Calandrino, R., Baló, T., Bordelo, J. A., Triboulet, S., Caruana, L., Klipfel, L., et al. (2025) · Reactions · doi:10.3390/reactions6010020 · Cited by 1
“Acting as chemical inducers of proximity (CIPs) [8], such organic compounds have been called molecular glues [9–13].”
Targeting oncogenic K-Ras mutants with a small-molecule degrader through Nedd4-1Preprint
Zeng, T., Jiang, T., Zhang, B., Zhang, T., Dai, W., Yin, X., Li, Y., Wu, C., Wu, Y., Chi, X., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.26.591418 · Cited by 1
Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone ComplexPreprint
Hayward, R. E., Berkeley, R. F., Gao, Z., Garhammer, M., Morizono, M. A., Njomen, E., Li, H., DeMeester, K. E., Cociorva, V., Herzik, M. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.20.683548 · Cited by 1
A biased allosteric modulator functions as a molecular glue to induce β 2 AR dimerizationPreprint
Shen, J., Peddada, T., Komolov, K. E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.21.683802 · Cited by 1
“Our findings extend the emerging paradigm of molecular glues in pharmacology 39,40 .”
Identification and SAR optimization of FBXO22-mediated TEAD Targeted Glue™ degradersPreprint
Fisher, M., Fletcher, A., Hamby, C., Miles, J., Ambler, M., Azevedo, A., Bisetto, S., Davies, C. T. R., Drouhin, P., Greger, L., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.21.719895
Targeting proteins to lysosomes with a chemical inducer of arginine methylation
(2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01744-9
Small Molecule Drugs in Cancer Therapy
Beer, P. A., & Okkenhaug, K. (2024) · Elsevier eBooks · doi:10.1016/b978-0-128-24465-4.00135-6
The next frontier in drug discovery: Unveiling the pharmacological potential of proximity inducers
Holmberg‐Douglas, N., Keenan, K. N., de Turiso, F. G.-L., Chekler, E. P., Shanmugasundaram, V., Riggs, J. R., & Zapf, C. W. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00018-2
Reengineering of a Proteomimetic Pan‐Ras Inhibitor into a Ras Degrader
Ongkingco, J. F., Hong, S. H., Toth, E. D., Nguyễn, T. T., & Arora, P. S. (2025) · Angewandte Chemie · doi:10.1002/ange.202507092
Guarnaccia, A. D., Sandoval, W. N., & Lill, J. R. (2025) · doi:10.1002/9781394236145.ch1
Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders
Zhuang, Z., Byun, W. S., Kozicka, Z., Donovan, K. A., Dwyer, B. G., Thornhill, A. M., Jones, H. M., Jiang, Z., Zhu, X., Fischer, E. S., et al. (2025) · Angewandte Chemie · doi:10.1002/ange.202508427
Molecular Glues as Activators for PPI
Qi, X. (2025) · Wiley eBooks · doi:10.1002/9783527845828.ch13
Cyclic peptides as ligands for competition binding assays
van Neer, R. H. P., Dranchak, P. K., Davis, A. K., Rai, G., & Inglese, J. (2025) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2025.08.021
Progress on molecular glue degraders
Chen, J., Deng, Z., Li, H., & Liu, L. (2025) · Scientia Sinica Chimica · doi:10.1360/ssc-2025-0228
Verhoef, C. J. A., Crowe, C., Nakasone, M. A., Basté, A. D. L. C., Harzing, T., Span, N. A. S., Sathe, G. J., Iso, K., Ottmann, C., Brunsveld, L., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.17.688825
Pennings, M. A. M., van den Bosch, M. A. W., Oberheide, A., Verhoef, C. J. A., Ottmann, C., Markvoort, A. J., Miley, G. P., & Brunsveld, L. (2025) · Angewandte Chemie · doi:10.1002/ange.202521678
Neo‐Cysteine Molecular Glues for Targeting Mutated SMAD4 Protein
Kumari, P., Oum, Y. H., Miller, E. J., Qui, M., Du, Y., Mou, H., Singh, R. K., Fu, H., & Mo, X. (2026) · Angewandte Chemie · doi:10.1002/ange.202512791
Targeted Protein Degradation by Repurposing Transmembrane E3 Ubiquitin Ligases
Cui, J., Qu, Q., & Pan, M. (2026) · ChemBioChem · doi:10.1002/cbic.202500870
Cancer biology and the principles of targeted cancer drug discovery
Davies, A., Jones, G., Krishnan, S., Krishnamoorthy, M., Maruggi, M., Kaneda, M., & Marjon, K. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00035-2
Pieńkowska, D. E., & Nowak, R. P. (2026) · Nature Chemical Biology · doi:10.1038/s41589-026-02187-0
Induced proximity strategies for modulating immune checkpoints in cancer immunotherapy
Wang, W., Li, Y., Zhang, W. Q., Zhang, Y., Zhang, K., Zhang, X. T., & Wang, T. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.118963 · Cited by 1
From Serendipity to Rationality: Expanding Druggability by Molecular Glue Discovery
Heppner, D. E., Kang, C., & Xu, W. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c01252 · Cited by 1
Metadata
- Authors
- Schreiber, S. L.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Schreiber, Stuart L.
- ORCID
- Schreiber, Stuart L.
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2024-06
- Volume
- 31
- Issue
- 6
- Pages
- 1050-1063
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W4399491693
- Semantic Scholar
- bdf154bc8ee372bd5acec4d6a1562bb429223611
- Cited by
- 112
- References
- 76
- Citations by year
- 2026: 41 · 2025: 62 · 2024: 9
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion, cc-by-nc-nd)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- molecular glues, bifunctional molecules, induced proximity, protein-protein interaction, fusion protein, missense mutations, post-translational modification, drug screening
- MeSH terms
- Humans, Protein Processing, Post-Translational, Proteins, Mutation, Missense
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