Design and linkage optimization of ursane-thalidomide-based PROTACs and identification of their targeted-degradation properties to MDM2 protein
Abstract
Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A-1F, in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B, connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC 50 value of 0.23 ~ 0.39 μM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.
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Compound 210, linked to POE-3, effectively inhibits growth of various cancer cells and substantially degrades MDM2 and increases p21 and PUMA proteins, suppressing proliferation and promoting apoptosis in A549 cells.
“They discovered that compound 210, linked to POE-3 (3-polyoxyether), effectively inhibited the growth of various cancer cells (Table 4). Further analysis using Western blotting demonstrated that compound 210 substantially degraded MDM2 and increased the expression of p21 and PUMA proteins, thereby suppressing cell proliferation and promoting apoptosis in A549 cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [504]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Qi, Z., Yang, G., Deng, T., Wang, J., Zhou, H., Popov, S. A., Shults, E. E., & Wang, C.
- Affiliations
- Institute of Chemical Industry of Forest Products (CN)
- Guangzhou University of Chinese Medicine (CN)
- Hunan University (CN)
- Novosibirsk Institute of Organic Chemistry (RU)
- Corresponding author
- Qi, Zhiwen
- Wang, Chengzhang
- Venue
- Bioorganic Chemistry
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 111
- Pages
- 104901
- ISSN
- 0045-2068 (ISSN-L)
- OpenAlex
- W3156299359
- Cited by
- 39
- References
- 45
- Citations by year
- 2026: 2 · 2025: 13 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 3
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Bioorganic Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Scientific Research Foundation of Hunan Provincial Education Department
- Chinese Academy of Forestry
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, ursolic acid, thalidomide, MDM2 degradation, triterpenoids, targeted protein degradation, ubiquitination, apoptosis, anticancer activity, A549 cells, p21, PUMA
- MeSH terms
- Antineoplastic Agents, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Structure-Activity Relationship, Thalidomide, Triterpenes, Drug Design, Molecular Structure, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-mdm2, Pentacyclic Triterpenes, Proteolysis
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