Cited by 54Cancer-related Molecular PathwaysSynthesis and biological activityNF-κB Signaling Pathways

Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway

Zhuang, Chunlin, Miao, Zhenyuan, Wu, Yuelin, Guo, Zizhao, Li, Jin, Yao, Jianzhong, Xing, Chengguo, Sheng, Chunquan +1 more·2014·Journal of Medicinal Chemistry

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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Crossref · 10.1021/jm401800k

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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”

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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
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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