Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction
Abstract
Although mutated Ras protein is well recognized as an important drug target, direct targeting Ras has proven to be a daunting task. Recent studies demonstrated that Ras protein needs PDEδ to relocate to plasma membrane to execute its signaling transduction function, which provides a new avenue for modulating the Ras protein. To find small molecules antagonizing the interactions between PDEδ and Ras, here we presented a successful application of fragment-based drug discovery of PDEδ inhibitors. Under the guidance of crystal structures, we are able to quickly optimize the initial fragment into highly potent inhibitors, with more than 2000-fold improvement in binding activity, which further adds to the arsenal towards the inhibition of Ras signaling in cancer therapy.
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The triazole PDEδ inhibitor effectively blocked the interaction between PDEδ and RAS protein, exhibiting over 2000-fold greater binding activity to PDEδ than deltarasin in the control group.
“Of these, the triazole PDEδ inhibitor effectively blocked the interaction between PDEδ and RAS protein, exhibiting over 2000-fold greater binding activity to PDEδ than deltarasin in the control group.346”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [346]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Chen, D., Chen, Y., Lian, F., Chen, L., Li, Y., Cao, D., Wang, X., Chen, L., Li, J., Meng, T., Huang, M., Geng, M., Shen, J., Zhang, N., & Xiong, B.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Huang, Min
- Zhang, Naixia
- Xiong, Bing
- ORCID
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 163
- Pages
- 597-609
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W2904686782
- Cited by
- 31
- References
- 29
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 4
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81330076, 81473094, 81402850)
- Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020345)
- Institutes for Drug Discovery and Development
- Chinese Academy of Sciences (CASIMM0120164002, CASIMM0120163013)
- Institutes for Drug Discovery and Development, Chinese Academy of Sciences (CASIMM0120164002, CASIMM0120163013)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- PDEδ, Ras, protein-protein interaction, triazole inhibitors, fragment-based drug discovery, Ras signaling, cancer therapy, small molecule inhibitors
- MeSH terms
- Cell Membrane, Humans, Neoplasms, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Protein Binding, Triazoles, Signal Transduction, ras Proteins, Cell Line, Tumor, Drug Discovery
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