2. Academic Validation
  3. KT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors

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

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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