Protein Knockdown Using Methyl Bestatin−Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins
Abstract
Induction of selective degradation of target proteins by small molecules (protein knockdown) would be useful for biological research and treatment of various diseases. To achieve protein knockdown, we utilized the ubiquitin ligase activity of cellular inhibitor of apoptosis protein 1 (cIAP1), which is activated by methyl bestatin (MeBS, 2). We speculated that formation of an artificial (nonphysiological) complex of cIAP1 and a target protein would be induced by a hybrid molecule consisting of MeBS (2) linked to a ligand of the target protein, and this would lead to cIAP1-mediated ubiquitination and subsequent proteasomal degradation of the target protein. To verify this hypothesis, we focused on cellular retinoic acid-binding proteins (CRABP-I and -II) and designed hybrid molecules (compounds 4) consisting of MeBS (2) coupled via spacers of various lengths to all-trans retinoic acid (ATRA, 3), a ligand of CRABPs. Compounds 4 induced selective loss of CRABP-I and -II proteins in cells. We confirmed that 4b induced formation of a complex of cIAP1 and CRABP-II in vitro and induced proteasomal degradation of CRABP-II in cells. When neuroblastoma IMR-32 cells were treated with 4b, the level of CRABP-II was reduced and cell migration was inhibited, suggesting potential value of CRABP-II-targeting therapy for controlling tumor metastasis. Our results indicate that 4b possesses sufficient activity, permeability, and stability in cells to be employed in cellular assays. Hybrid molecules such as 4 should be useful not only as chemical tools for studying the biological/physiological functions of CRABPs but also as candidate therapeutic agents targeting CRABPs.
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PROTAC treatment of cells expressing c-IAP1 and either CRABP-1 or CRABP-2 reduced levels of both c-IAP1 and either CRABP protein.
“PROTAC treatment of cells expressing c-IAP1 and either CRABP-1 or CRABP-2 reduced levels of both c-IAP1 and either CRABP protein.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [99]
Degradation of CRABP-2 resulted in reduced cell migration in neuroblastoma.
“Using the PROTAC on neuroblastoma, degradation of CRABP-2 resulted in reduced cell migration [99].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [99]
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- Authors
- Itoh, Y., Ishikawa, M., Naito, M., & Hashimoto, Y.
- Affiliations
- National Institute of Health Sciences (JP)
- Corresponding author
- Hashimoto, Yuichi
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-04-06
- Volume
- 132
- Issue
- 16
- Pages
- 5820-5826
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W1995079678
- Cited by
- 404
- References
- 64
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 34 · 2023: 39 · 2022: 63 · 2021: 46 · 2020: 53 · 2019: 30 · 2018: 26 · 2017: 22 · 2016: 15 · 2015: 5 · 2014: 6 · 2013: 3 · 2012: 3
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21651092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- protein knockdown, cIAP1, ubiquitin ligase, proteasomal degradation, cellular retinoic acid-binding protein, CRABP I, CRABP2, hybrid molecules, all-trans retinoic acid, metastasis, cell migration
- MeSH terms
- Cell Movement, Humans, Leucine, Ligands, Neoplasm Invasiveness, Tretinoin, Drug Design, Receptors, Retinoic Acid, Cell Line, Tumor, Inhibitor of Apoptosis Proteins, Ubiquitination
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