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. 2025 Oct 5:295:117793.
doi: 10.1016/j.ejmech.2025.117793. Epub 2025 May 21.

Characterization of a dual degrader of MDM2 and GSPT1

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

Characterization of a dual degrader of MDM2 and GSPT1

Ira Tandon et al. Eur J Med Chem. .

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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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: W.T. is the shareholder of Chimergen Therapeutics Inc., NovaCure Biosciences Holding Inc., and MolTenon Biosciences Inc.

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