Cited by 201Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

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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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Yang, Jiuling, Li, Yangbing, Aguilar, Angelo, Liu, Zhaomin, Yang, Chao-Yie, Wang, Shaomeng·2019·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.9b00846PMC PMC7354697

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Abstract

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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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
ORCID: Yang, Jiuling
Aguilar, Angelo
Liu, Zhaomin
Yang, Chao-Yie
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
DOI: 10.1021/acs.jmedchem.9b00846
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: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
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
Physical Sciences › Chemistry › Organic Chemistry › 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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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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