bims-midomi Biomed News
on MDM2 and mitochondria
Issue of 2025–03–02
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Optimal Stapling of a Helical Peptide-Foldamer Hybrid Using a C-terminal 4-Mercaptoproline Enhances Protein Surface Recognition and Cellular Activity.
  2. MDM2 inhibitors induce apoptosis by suppressing MDM2 and enhancing p53, Bax, Puma and Noxa expression levels in imatinib‑resistant chronic myeloid leukemia cells.
  1. Chemistry. 2025 Feb 27. e202403330
    Optimal Stapling of a Helical Peptide-Foldamer Hybrid Using a C-terminal 4-Mercaptoproline Enhances Protein Surface Recognition and Cellular Activity.
    Maxime Neuville, Mathieu Bourgeais, Jérémie Buratto, Claire Saragaglia, Bo Li, Isabel Galeano-Otero, Laura Mauran, Laetitia Varajao, Sébastien R Goudreau, Brice Kauffmann, Emmanuelle Thinon, Morgane Pasco, Abdel-Majid Khatib, Gilles Guichard.
      Structural analysis of a co-crystal of a helically-folded peptide-foldamer hybrid in complex with hDM2 E3 ubiquitin ligase, revealed a unique orientation for the C-terminal proline with the pyrrolidine ring pointing backwards in the sequence, and suggested new opportunities for macrocyclization. In particular, we found that the C-terminal prolyl residue could be replaced by its (2S,4S)-4-mercaptoprolyl analogue for optimal bisthioether crosslinking with a cysteine residue installed at position 4 in the sequence. The resulting i,i+7 stapled peptide-foldamer is a high-affinity binder to hDM2, is cell permeable and restores the p53 signalling pathway in p53wt cancer cells. The co-crystal structure of hDM2 and the stapled peptide-foldamer hybrid was determined at 1.84 Å, fully validating the original design and further highlighting the potential of cis-4-mercaptoproline in the context of peptide and foldamer stapling.
    Keywords:  Foldamers; Helical structures; Macrocycles; Peptidomimetics; Protein-protein interactions
    DOI:  https://doi.org/10.1002/chem.202403330
  2. Biomed Rep. 2025 Apr;22(4): 65
    MDM2 inhibitors induce apoptosis by suppressing MDM2 and enhancing p53, Bax, Puma and Noxa expression levels in imatinib‑resistant chronic myeloid leukemia cells.
    Akihiro Kimura, Masanobu Tsubaki, Teruki Obana, Taira Matsuo, Rie Komori, Noriaki Nagai, Tetsushi Yamamoto, Shozo Nishida.
      Activation of BCR::ABL1 tyrosine kinase is the main pathogenic mechanism underlying chronic myeloid leukemia (CML) in 90% of affected patients. The prognosis for individuals with CML who receive treatment with BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib, is promising, with a 5-year survival rate of >90%. However, unfortunately, 20-30% of patients who are treated with imatinib may become resistant to the BCR::ABL1 TKIs. The objective of the present study was to determine whether inhibitors of E3 ubiquitin-protein ligase Mdm2 (MDM2), a regulator of p53 that promotes apoptosis and is highly expressed in CML, could induce cell death in imatinib-resistant CML cells. Apoptosis and cell viability were evaluated using Annexin-V-positive cell count and caspase-3 activity, as well as trypan blue dye exclusion assay. Expression levels of MDM2, p53, Bax, Puma, Noxa, p21, and cleaved caspase-3 were determined via western blotting. MDM2 levels in both the cytoplasm and nucleus were found to be ~3-fold higher in K562/IR cells compared with K562 cells, while the levels of p53 in both cell structures were markedly lower. In addition, an examination of a publicly accessible database revealed that the levels of MDM2 were evidently greater in patients who did not respond to imatinib compared with those who did respond to the drug. NSC-66811 and Nutlin-3, MDM2 inhibitors, increased the percentage of Annexin-positive cells in K562/IR cells by 43 and 62% at concentrations of 10 and 25 µM, respectively. Furthermore, the MDM2 inhibitors increased the levels of Bax, Puma, Noxa, and p21 by increasing the expression of p53 and decreasing the expression of MDM2 in K562/IR cells. Additionally, pifithrin-α, a p53 inhibitor, suppressed MDM2 inhibitor-induced cell death in K562/IR cells. Overall, the findings of the present study highlight the therapeutic potential of MDM2 inhibitors for imatinib-resistant CML.
    Keywords:  E3 ubiquitin-protein ligase Mdm2; chronic myeloid leukemia; imatinib resistance; p53
    DOI:  https://doi.org/10.3892/br.2025.1943
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