ArticlePloS one2013
In vitro selection of mutant HDM2 resistant to Nutlin inhibition.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- Engineering cell-free systems by chemoproteomic-assisted phenotypic screening.RSC chemical biology · 2024Article
- Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists.Cancers · 2019Review
- MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388).OncoTargets and therapy · 2019Review
- Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells.Cancers · 2018Article
- Synthetic 10FN3-based mono- and bivalent inhibitors of MDM2/X function.Protein engineering, design & selection : PEDS · 2018Article
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- Functional characterization of p53 pathway components in the ancient metazoan Trichoplax adhaerens.Scientific reports · 2016Article
- Pharmacological activation of wild-type p53 in the therapy of leukemia.Experimental hematology · 2016Review
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- Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides.Oncotarget · 2016Article
- The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans.Genes & development · 2016Article
- Energetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction.PloS one · 2016Article
- Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.Chemistry & biology · 2014Review
- Drugging the p53 pathway: understanding the route to clinical efficacy.Nature reviews. Drug discovery · 2014Review
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Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
HDM2 binds to the p53 tumour suppressor and targets it for proteosomal degradation. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2 and abrogates its repressive function. Using a novel in vitro selection methodology, we simulated the emergence of resistance by evolving HDM2 mutants capable of binding p53 in the presence of Nutlin concentrations that inhibit the wild-type HDM2-p53 interaction. The in vitro phenotypes were recapitulated in ex vivo assays measuring both p53 transactivation function and the direct p53-HDM2 interaction in the presence of Nutlin. Mutations conferring drug resistance were not confined to the N-terminal p53/Nutlin-binding domain, and were additionally seen in the acidic, zinc finger and RING domains. Mechanistic insights gleaned from this broad spectrum of mutations will aid in future drug design and further our understanding of the complex p53-HDM2 interaction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.