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Updated: Jun 12, 2025
Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Characterization of a dual degrader of MDM2 and GSPT1
Ira Tandon1, Paulina N Esguerra1, Chunrong Li1
1Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
Abstract:
Murine double minute 2 (MDM2) has long been a therapeutic target to stabilize and upregulate wild-type tumor protein 53 (p53) in cancer. We initially reported WB156 as a degrader of MDM2 that can upregulate p53 levels in acute leukemia. To further evaluate the therapeutic potential of WB156, we tested it in a variety of cancers alongside another reported MDM2 degrader. We found that WB156 is active in wild-type and mutant p53-bearing leukemias due to its ability to degrade both MDM2 and G1 To S Phase Transition 1 (GSPT1) protein. In cancers that are non-responsive to MDM2 degradation alone, WB156 acts as a GSPT1 degrader to induce anti-proliferative effects. Here, we report the first MDM2/GSPT1 dual degrader that also upregulates p53 levels.
Insights
WB156 is a novel dual degrader targeting MDM2 and GSPT1, effectively upregulating p53. This compound shows anti-cancer activity in various cancers, including leukemias with wild-type and mutant p53.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Murine double minute 2 (MDM2) is a validated therapeutic target for stabilizing tumor protein 53 (p53) in cancer.
- Previous research identified WB156 as an MDM2 degrader that increases p53 levels in acute leukemia.
Purpose of the Study:
- To evaluate the broader therapeutic potential of WB156 across various cancer types.
- To investigate the mechanism of action of WB156, particularly in cancers resistant to MDM2 degradation alone.
Main Methods:
- Testing WB156 in diverse cancer models.
- Comparative analysis with another known MDM2 degrader.
- Assessing protein degradation of MDM2 and G1 To S Phase Transition 1 (GSPT1).
Main Results:
- WB156 demonstrated efficacy in both wild-type and mutant p53-bearing leukemias.
- WB156 functions as a dual degrader of MDM2 and GSPT1.
- In cancers unresponsive to MDM2 degradation, WB156 induced anti-proliferative effects via GSPT1 degradation.
Conclusions:
- WB156 is the first reported dual MDM2/GSPT1 degrader.
- WB156 upregulates p53 levels and exhibits anti-cancer activity through dual degradation pathways.
- WB156 represents a promising therapeutic candidate for a range of cancers.
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