A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins.

@article{Soares2015ATO,
  title={A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins.},
  author={Joana Soares and Liliana Raimundo and Nuno A. L. Pereira and Daniel J. V. A. dos Santos and Maria P{\'e}rez and Gl{\'o}ria Queir{\'o}z and Mariana Le{\~a}o and Maria M. M. Santos and Luc{\'i}lia Sara{\'i}va},
  journal={Pharmacological research},
  year={2015},
  volume={95-96},
  pages={
          42-52
        }
}
Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule
TLDR
The identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type and mut p53, using a yeast-based screening strategy, represents a promissing starting point for the development of effective p53-reactivating drugs.
DIMP53‐1: a novel small‐molecule dual inhibitor of p53–MDM2/X interactions with multifunctional p53‐dependent anticancer properties
TLDR
DIMP53‐1 is a novel p53 activator, which potentially binds to p53 inhibiting its interaction with MDM2 and MDMX, and is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application.
Medicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction
TLDR
The knowledge of structural requirements crucial to the development of small‐molecule inhibitors of the p53–MDM2/MDMX interactions has enabled the identification of novel antitumor agents with improved in vivo efficacy.
Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53
TLDR
The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.
A Diarylpentanoid with Potential Activation of the p53 Pathway: Combination of in silico Screening Studies, Synthesis, and Biological Activity Evaluation
TLDR
The antiproliferative effect of this compound was associated with induction of cell cycle arrest, apoptosis, PARP cleavage and increased p53 and its transcriptional targets, p21 and PUMA in HCT116 cells.
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References

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Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53-MDM2 interaction.
  • J. Soares, Nuno A. L. Pereira, L. Saraíva
  • Biology, Chemistry
    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2015
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
TLDR
Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.
Efficient reactivation of p53 in cancer cells by a dual MdmX/Mdm2 inhibitor.
TLDR
It is demonstrated that a dual small-molecule antagonist of Mdm2/MdmX can efficiently reactivate the p53 pathway in model cancer cells overexpressing MdmX and/or MDM2.
Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.
TLDR
The discovery of AM-8553, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency.
Hdmx Modulates the Outcome of P53 Activation in Human Tumor Cells*
TLDR
Tumors that express wild-type P53 provide a target for therapies designed to reactivate P53 function, and the role of Hdmx expression in sensitivity to Nutlin is evaluated, implying that HDMx is an important determinant of the outcome of P53 activation.
Novel simplified yeast‐based assays of regulators of p53–MDMX interaction and p53 transcriptional activity
TLDR
It is shown that the reported wild‐type (wt) p53‐induced yeast growth inhibition and cell cycle arrest is associated with actin depolarization and with an increase of actin mRNA and protein expression levels.
Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3.
TLDR
It is shown that Nutlin-3 efficiently induces apoptosis and diminishes long-term survival of human fibroblasts transformed in vitro by HDM2 but not HdmX, establishing Hdm2 and HDMX as independent therapeutic targets with respect to reactivating wild-type p53 as a means for cancer therapy.
Drugging the p53 pathway: understanding the route to clinical efficacy
TLDR
The current state of the development of p53 pathway modulators and new pathway targets that have emerged are described.
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