Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression
Open accessAbstract
Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC 50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC 50 values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.
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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 [127]
MD-224 potently induces rapid degradation of MDM2 in leukemia cells.
“MD-224 potently induced rapid degradation of MDM2 in leukemia cells.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [46]
MD-224 achieves complete and durable tumor regression in a RS4-11 xenograft model by intravenous administration.
“Moreover, MD-224 is capable of achieving complete and durable tumor regression in a RS4-11 xenograft model by intravenous administration.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [46]
PROTACs directed to oncology targets can induce durable responses in xenograft models.
“PROTACs directed to oncology targets can induce durable responses in xenograft models 19 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [19]
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- Authors
- Li, Y., Yang, J., Aguilar, A., McEachern, D., Przybranowski, S., Liu, L., Yang, C.-Y., Wang, M., Han, X., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-12-10
- Volume
- 62
- Issue
- 2
- Pages
- 448-466
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6545112
- OpenAlex
- W2904458560
- Cited by
- 312
- References
- 36
- Citations by year
- 2026: 23 · 2025: 46 · 2024: 37 · 2023: 41 · 2022: 49 · 2021: 32 · 2020: 48 · 2019: 35 · 2018: 1
- FWCI
- 10.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (1R01CA208267, P30 CA046592)
- Oncopia Therapeutics LLC
- Rogel Cancer Center, University of Michigan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, MDM2, p53, leukemia, RS4, tumor regression, small-molecule degraders, anticancer agents, xenograft tumor model
- MeSH terms
- Animals, Humans, Indoles, Leukemia, Proto-Oncogene Proteins, Spiro Compounds, Drug Design, Tumor Suppressor Protein p53, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Apoptosis Regulatory Proteins, Mice, Proto-Oncogene Proteins c-mdm2, Proteolysis
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