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.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
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Supplementary data

Supplemental Figure 1

Supplemental Figure 1: Chemical structures of (A) Compound 1, a KT 253 analog that lacks ability to engage cereblon (CRBN), (B) Compound 2, the warhead of KT 253 that engages MDM2, and (C) DS-3032, a small-molecule MDM2/p53 interaction inhibitor.

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Supplemental Figure 2

Supplemental Figure 2: Targeted proteomics analysis of MDM2 levels in MV4;11 AML cells shows that 150 nM KT 253 can achieve degradation of MDM2 within 1 hour posttreatment.

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Supplemental Figure 3

Supplemental Figure 3: Short term exposures with KT-253 sufficient for growth inhibition compared with MDM2 SMIs.

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Supplemental Figure 4

Supplemental Figure 4: A functional p53 is required for growth inhibition with KT-253.

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Supplemental Figure 5

Supplemental Figure 5: A single dose of KT-253 more robustly induces p53 targets compared with exposure matched weekly dosing regimen.

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Supplemental Figure 6

Supplemental Figure 6: KT 253 activity in p53 WT ABC subtype DLBCL model but not p53 mutated ABC subtype DLBCL model.

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Supplemental Figure 7

Supplemental Figure 7: A single dose of KT 253 shows strong single-agent activity in a venetoclax resistant patient-derived AML model.

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Supplemental Table 1

Supplemental Table 1: Cell lines and reagents

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Supplemental Table 2

Supplemental Table 2: Genes and TaqMan Gene Expression Assay IDs used for RT-qPCR assays

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Supplemental Table 3

Supplemental Table 3: KT-253 shows picomolar growth inhibition potency compared with other MDM2 small molecule inhibitors.

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Supplemental Table 4

Supplemental Table 4: KT-253 shows potent growth inhibition and caspase activation across a panel of p53 wild-type hematologic cell lines.

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Supplemental Table 5

Supplemental Table 5: Activity of KT-253 in AML patient-derived xenograft models.

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