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
  • 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: [email protected].
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.
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