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Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Luis A Carvajal1, Daniela Ben Neriah1, Adrien Senecal2

  • 1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Science Translational Medicine
|April 13, 2018
PubMed

Insights

Dual inhibition of MDMX and MDM2 with ALRN-6924 restores tumor suppressor p53 activity, showing significant anti-leukemic effects in acute myeloid leukemia (AML) models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The tumor suppressor p53 is crucial for preventing cancer but is often inactivated by MDM2 and MDMX inhibitors.
  • MDM2 and MDMX are frequently overexpressed in acute myeloid leukemia (AML) and other cancers, leading to p53 inactivation.
  • Current therapies targeting this pathway are limited to MDM2 inhibitors, which do not affect MDMX.

Purpose of the Study:

  • To evaluate the therapeutic potential of dual MDMX/MDM2 inhibition using the stapled peptide ALRN-6924 in AML.
  • To investigate the mechanism of action of ALRN-6924 in restoring p53 activity and its anti-leukemic effects.

Main Methods:

  • Utilized a stapled α-helical peptide (ALRN-6924) for dual MDMX and MDM2 inhibition.
  • Assessed p53-dependent transcription activation at single-cell and single-molecule levels.
  • Evaluated ALRN-6924's effects on cell proliferation, cell cycle arrest, apoptosis, and clonogenic capacity in leukemia cells and AML xenograft models.

Main Results:

  • ALRN-6924 demonstrated robust activation of p53-dependent transcription and on-target activity in leukemia cells.
  • Dual MDMX/MDM2 inhibition by ALRN-6924 effectively inhibited proliferation, induced cell cycle arrest and apoptosis in AML cell lines and patient cells.
  • ALRN-6924 treatment significantly improved survival rates in AML xenograft models.

Conclusions:

  • Dual MDMX/MDM2 inhibition with ALRN-6924 shows significant antileukemic effects in AML.
  • ALRN-6924 restores p53 tumor suppressor activity, offering a promising therapeutic strategy for AML and other cancers with wild-type p53.

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