KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors.

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 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 small-molecule MDM2/p53 interaction inhibitors 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 and acute lymphoblastic leukemia xenograft models. Additionally, a single intravenous dose of KT-253 in combination with standard-of-care venetoclax overcame venetoc

SUBMITTER: Chutake YK 

PROVIDER: S-EPMC11962396 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature