Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway
Abstract
Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/β. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).
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By employing structure-based virtual screening, they identified a quinazolinone fragment, hit 4 (Kd = 467 ± 65 nM), with two optical isomers that acted on different "hot spots" of PDEδ.
“By employing structure-based virtual screening, they identified a quinazolinone fragment, hit 4 (Kd = 467 ± 65 nM), with two optical isomers that acted on different “hot spots” of PDEδ.349–352”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [350]
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- Authors
- Zhuang, C., Miao, Z., Wu, Y., Guo, Z., Li, J., Yao, J., Xing, C., Sheng, C., & Zhang, W.
- Affiliations
- University of Minnesota (US)
- Second Military Medical University (CN)
- Corresponding author
- Miao, Zhenyuan
- Sheng, Chunquan
- Zhang, Wannian
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-01-24
- Volume
- 57
- Issue
- 3
- Pages
- 567-577
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2319546094
- Cited by
- 50
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 2 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 1 · 2014: 5
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- p53-MDM2 interaction, NF-κB signaling, small molecule inhibitors, IκBα phosphorylation, IKKα/β, p65 nuclear translocation, oral bioavailability, A549 xenograft, cancer therapeutics, dual inhibitors
- MeSH terms
- Administration, Oral, Animals, Antineoplastic Agents, Biological Availability, Cell Nucleus, Drug Screening Assays, Antitumor, Humans, Male, Mice, Nude, Neoplasm Transplantation, Pyrazoles, Pyrroles, Pyrrolidinones, Structure-Activity Relationship, Signal Transduction, Tumor Suppressor Protein p53, NF-kappa B, Rats, Sprague-Dawley, Active Transport, Cell Nucleus, Cell Line, Tumor, Mice, Rats, Proto-Oncogene Proteins c-mdm2, Heterografts
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