KT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors

  • Mol Cancer Ther. 2024 Dec 9. doi: 10.1158/1535-7163.MCT-24-0306.
Yogesh K Chutake  1 ,  Michele F Mayo  1 ,  Nancy Dumont  1 ,  Jessica Filiatrault  1 ,  Susanne B Breitkopf  1 ,  Patricia Cho  1 ,  Dapeng Chen  1 ,  Vaishali S Dixit  1 ,  William R Proctor  2 ,  Eric W Kuhn  1 ,  Sarah Bollinger Martinez  1 ,  Alice A McDonald  1 ,  Jianfeng Qi  1 ,  Kan-Nian Hu  1 ,  Rahul Karnik  1 ,  Joseph D Growney  1 ,  Kirti Sharma  1 ,  Stefanie S Schalm  1 ,  Ashwin M Gollerkeri  1 ,  Nello Mainolfi  1 ,  Juliet A Williams  1 ,  Matthew M Weiss  1
Affiliations
  • 1. Kymera Therapeutics, Inc., Watertown, Massachusetts, United States.
  • 2. Kymera Therapeutics, Inc., United States.
PMID: 39648478 DOI: 10.1158/1535-7163.MCT-24-0306
Abstract

Murine double minute 2 (MDM2) is an E3 Ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors (SMIs) have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT 253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with SMIs and induces Apoptosis in a range of hematologic and solid tumor lines. A single intravenous dose of KT 253 triggered rapid Apoptosis and sustained tumor regression in p53 wild-type acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) xenograft models. Additionally, a single intravenous dose of KT 253 in combination with standard-of-care (SoC) venetoclax, overcame venetoclax resistance in an AML xenograft model. The data herein define the therapeutic potential of KT-253 and support its clinical development in a range of hematologic and solid p53 wild-type (WT) malignancies, as a monotherapy and in combination with SoC agents.

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