KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
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 venetoclax resistance in an acute myeloid leukemia 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 malignancies, as a monotherapy and in combination with standard-of-care agents.
Authors
- Nancy Dumont (ORCID: https://orcid.org/0000-0002-6565-0851)
- Stefanie S. Schalm (ORCID: https://orcid.org/0009-0002-1303-3699)
- Sarah Bollinger Martinez (ORCID: https://orcid.org/0009-0001-6270-6901)
- Matthew M. Weiss (ORCID: https://orcid.org/0000-0002-2559-2183)
- Patricia Cho (ORCID: https://orcid.org/0000-0002-6508-5645)
- Kirti Sharma (ORCID: https://orcid.org/0000-0003-3704-1466)
- William Proctor
- Yogesh K. Chutake (ORCID: https://orcid.org/0009-0007-0531-8877)
- Rahul Karnik (ORCID: https://orcid.org/0000-0002-0400-635X)
- Michele Mayo (ORCID: https://orcid.org/0009-0005-0359-7900)
- Nello Mainolfi (ORCID: https://orcid.org/0009-0002-9398-5859)
- Ashwin Gollerkeri (ORCID: https://orcid.org/0000-0001-8215-4318)
- Eric Kuhn (ORCID: https://orcid.org/0000-0001-6631-1950)
- Susanne B. Breitkopf
- Vaishali Dixit (ORCID: https://orcid.org/0000-0002-2994-8351)
- Jianfeng Qi (ORCID: https://orcid.org/0009-0003-1456-0770)
- Joseph D. Growney
- Jessica Filiatrault (ORCID: https://orcid.org/0000-0002-1875-4949)
- Juliet Williams
- Kan‐Nian Hu (ORCID: https://orcid.org/0009-0002-3920-4521)
- Dapeng Chen
- Alice McDonald (ORCID: https://orcid.org/0009-0006-6927-6226)
Institutions
- Woomera Therapeutics (US)
Publication Details
- Journal
- Molecular Cancer Therapeutics
- Published
- 2024-12-07
- DOI
- https://doi.org/10.1158/1535-7163.mct-24-0306
- Citations
- 15
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 4.24