2. Academic Validation
  3. Characterization of a dual degrader of MDM2 and GSPT1

Characterization of a dual degrader of MDM2 and GSPT1

  • Eur J Med Chem. 2025 Oct 5:295:117793. doi: 10.1016/j.ejmech.2025.117793.
Ira Tandon 1,  Paulina N Esguerra 1,  Chunrong Li 1,  Huan Sun 2,  Ka Yang 2,  Zhongrui Zhang 1,  Junmin Peng 2,  Weiping Tang 3
Affiliations

Affiliations

  • 1 Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
  • 2 Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 3 Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53705, USA. Electronic address: weiping.tang@wisc.edu.
PMID: 40440791 DOI: 10.1016/j.ejmech.2025.117793
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.

Keywords

Dual degrader; GSPT1; MDM2; PROTACs; p53.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174266
    MDM2/GSPT1 Degrader