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MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53

Mengyang Chang1, Feng Gao2, Jing Chen2

  • 1Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.

Acta Materia Medica
|March 13, 2023
PubMed

Insights

New PROTACs targeting BCL-XL degradation utilize MDM2 as the E3 ligase. The compound BMM4 selectively degrades BCL-XL, stabilizes p53, and shows synergistic effects with ABT-199 in cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeting anti-apoptotic protein BCL-XL is a key cancer therapy strategy.
  • Existing Proteolysis-Targeting Chimeras (PROTACs) for BCL-XL primarily use VHL or CRBN E3 ligases.
  • There is a need for novel E3 ligases in PROTAC development for BCL-XL degradation.

Purpose of the Study:

  • To develop novel Proteolysis-Targeting Chimeras (PROTACs) for BCL-XL degradation using MDM2 as the E3 ligase.
  • To design, synthesize, and evaluate MDM2-BCL-XL PROTACs with varying linker lengths.
  • To investigate the dual-functional capability of these PROTACs, including p53 stabilization.

Main Methods:

  • Design and synthesis of three MDM2-BCL-XL PROTACs based on Nutlin-3 and ABT-263 scaffolds.
  • In vitro evaluation of PROTACs in U87, A549, and MV-4-11 cancer cell lines.
  • Assessment of BCL-XL degradation, p53 stabilization, and antiproliferative activity, including combination studies with ABT-199.

Main Results:

  • The compound BMM4 demonstrated potent and selective degradation of BCL-XL.
  • BMM4 effectively stabilized tumor suppressor p53 in tested cancer cell lines.
  • Combination therapy with BMM4 and BCL-2 inhibitor ABT-199 exhibited synergistic antiproliferative effects.

Conclusions:

  • MDM2-BCL-XL PROTACs represent a novel approach for targeted protein degradation.
  • BMM4 is a promising dual-functional molecule for cancer therapy, degrading BCL-XL and stabilizing p53.
  • These findings offer an alternative strategy for cancer treatment through targeted protein degradation.
Keywords:
BCL-XLMDM2 E3 ligasePROTACtargeted protein degradation

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