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

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

Yogesh K. Chutake, Michele F. Mayo, Nancy Dumont, Jessica Filiatrault, Susanne B. Breitkopf, Patricia Cho, Dapeng Chen, Vaishali S. Dixit, William R. Proctor, Eric W. Kuhn, Sarah Bollinger Martinez, Alice A. McDonald, Jianfeng Qi, Kan-Nian Hu, Rahul Karnik, Joseph D. Growney, Kirti Sharma, Stefanie S. Schalm, Ashwin M. Gollerkeri, Nello Mainolfi, Juliet A. Williams, Matthew M. Weiss

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.