Mechanisms of Molecular Glue Degraders and Their Applications in Hematological Malignancies
DOI:
https://doi.org/10.61173/gvsgps62Keywords:
Molecular glue degraders, E3 ubiquitin ligase, Hematological malignancies, Targeted protein degradation, Resistance mechanismsAbstract
Molecular glue degraders (MGDs) belong to a category of small-molecule compounds that bring E3 ubiquitin ligases and target proteins close to each other, thereby initiating the ubiquitination process and the subsequent breakdown of the target proteins. In the past few years, these substances have shown considerable therapeutic potential in the treatment of hematological malignancies. This review comprehensively summarizes the action mechanisms of MGDs, sorts out their preclinical and clinical advances in hematological cancers, and explores the existing challenges as well as future development directions. MGDs offer a new approach for cancer treatment, yet further research is needed to clarify their resistance mechanisms and improve the precision of target selection.
References
[1] Sasso, J. M., Tenchov, R., Wang, D., et al. (2023). Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry, 62(3), 601–623.
[2] Lemaitre, T., Cornu, M., Schwalen, F., et al. (2024). Molecular glue degraders: exciting opportunities for novel drug discovery. Expert opinion on drug discovery, 19(4), 433–449.
[3] Tan, X., Huang, Z., Pei, H., et al.(2024). Molecular gluemediated targeted protein degradation: A novel strategy in smallmolecule drug development. iScience, 27(9), 110712.
[4] Dewey, J. A., Delalande, C., Azizi, S. A.,et al.(2023). Molecular Glue Discovery: Current and Future Approaches. Journal of medicinal chemistry, 66(14), 9278–9296.
[5] Kang, C., & Xu, W. (2025). Leveraging structural and computational biology for molecular glue discovery. Journal of Medicinal Chemistry, 68(3).
[6] Oleinikovas, V., Gainza, P., Ryckmans, T.,et al.(2024). From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation. Annual review of pharmacology and toxicology, 64, 291–312.
[7] Ming, H., Li, B., Jiang, J.,et al. (2023). Protein degradation: expanding the toolbox to restrain cancer drug resistance. Journal of hematology & oncology, 16(1), 6.
[8] Krönke, J., Udeshi, N. D., Narla, A., et al. (2014). Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science (New York, N.Y.), 343(6168), 301–305.
[9] National Cancer Institute. (2021). A phase II clinical trial of E7820 for patients with relapsed/refractory myeloid malignancies with mutations in splicing factor genes (NCT05024994). https:// clinicaltrials.gov/study/NCT05024994
[10] Kohsaka, S., Yagishita, S., Shirai, Y., et al.(2024). A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency. NPJ precision oncology, 8(1), 117.
[11] Słabicki, M., Yoon, H., Koeppel, J., et al.(2020). Smallmolecule-induced polymerization triggers degradation of BCL6. Nature, 588(7836), 164–168.
[12] Feng, Y., Hu, X., & Wang, X. (2024). Targeted protein degradation in hematologic malignancies: clinical progression towards novel therapeutics. Biomarker research, 12(1), 85.
[13] Bird, S., & Pawlyn, C. (2023). IMiD resistance in multiple myeloma: current understanding of the underpinning biology and clinical impact. Blood, 142(2), 131–140.
[14] Hartley-Brown, M. A., Mo, C. C., Nadeem, O., et al.(2024). Mezigdomide-A Novel Cereblon E3 Ligase Modulator under Investigation in Relapsed/Refractory Multiple Myeloma. Cancers, 16(6), 1166.
[15] Lonial, S., Dimopoulos, M. A., Berdeja, J. G., et al. (2025). EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma. Future oncology (London, England), 21(14), 1761–1769.
[16] Karagoz, K., Stokes, M., Ortiz-Estévez, M., et al.(2022). Multiple Myeloma Patient Tumors With High Levels of Cereblon Exon-10 Deletion Splice Variant Upregulate Clinically Targetable Pro-Inflammatory Cytokine Pathways. Frontiers in genetics, 13, 831779.
[17] Hu, Y., Yan, Y., Wang, J., et al.(2024). Molecular glue degrader for tumor treatment. Frontiers in Oncology, 14, 1512666.
[18] Celgene. (2020). A Safety and Efficacy Study of CC- 90009 Combinations in Subjects With Acute Myeloid Leukemia(NCT04336982) https://clinicaltrials.gov/ct2/show/ NCT04336982
[19] Jimenez, C., Peng, S., Narla, R. K., et al.(2024). BMS- 986397, a first-in-class molecular glue degrader of casein kinase 1α (CK1α) for the treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) harboring functional TP53. Blood, 144(Suppl 1), 4142.
[20] Nowakowski, G., Hoffmann, M., Westin, J., et al. (2025). Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD™ agent, plus R-CHOP in patients (Pts) with previously untreated aggressive B-cell lymphoma (a-BCL): 24-month efficacy results [Abstract 476]. Blood, 146(Supplement 1), 476.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 by the authors.

This work is licensed under a Creative Commons Attribution 4.0 International License.
