Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders
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Inducing protein degradation by proteolysis targeting chimeras (PROTACs) has gained tremendous momentum for its promise to discover and develop new therapies. Based upon our previously reported PROTAC MDM2 degraders, we have designed and synthesized additional analogues. Surprisingly, we found that simple structural modifications of MD-222, a bona fide MDM2 PROTAC degrader, converts it into a “molecular glue”, as exemplified by MG-277 . MG-277 induces only moderate MDM2 degradation and fails to activate wild-type p53 but is highly potent in inhibition of tumor cell growth in a p53-independent manner. Our mechanistic investigation established that MG-277 is not a PROTAC MDM2 degrader but instead works as a molecular glue, inducing degradation of a translation termination factor, GSPT1 to achieve its potent anticancer activity. Our study provides the first example that simple structural modifications can convert a bona fide PROTAC degrader into a molecular glue compound, which has a completely different mechanism of action.
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MG-277 (209) targets MDM2 for degradation and acts as a molecular glue to facilitate degradation of GSPT1.
“Subsequently, the same group discovered a novel compound, MG-277 (209), targeting MDM2 for degradation while also acting as a “molecular glue” to facilitate the degradation of an additional target protein, GSPT1 (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [503]
GSPT1 is responsible for off-target effects of PROTAC molecules that recruit CRBN.
“It has also been reported that GSPT1 is responsible for off-target effects for PROTAC molecules that recruit CRBN [42–44].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [44]
Possible off-target effects may arise from the E3 ligase ligand side, such as GSPT1 degradation.
“However, possible off-target effects may arise from the E3 ligase ligand side, such as the degradation of GSPT1 in this work and others[42–44].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [44]
Targeted MDM2 degradation has the potential to reduce dose-dependent hematological toxicity of MDM2 inhibitors.
“Targeted MDM2 degradation also had the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors [124–128].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [124]
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Self-citation
- Authors
- Yang, J., Li, Y., Aguilar, A., Liu, Z., Yang, C.-Y., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-09-27
- Volume
- 62
- Issue
- 21
- Pages
- 9471-9487
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7354697
- OpenAlex
- W2976352578
- Cited by
- 190
- References
- 45
- Citations by year
- 2026: 17 · 2025: 39 · 2024: 31 · 2023: 23 · 2022: 30 · 2021: 25 · 2020: 24 · 2019: 1
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health and Human Services (1R01CA208267, P30 CA046592)
- University of Michigan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTAC degraders, molecular glues, MDM2, GSPT1, structural modification, protein degradation, translation termination factor, anticancer drug design
- MeSH terms
- Antineoplastic Agents, Humans, Models, Molecular, Peptide Termination Factors, Protein Conformation, Drug Design, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2, Proteolysis
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