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

IF 5.3 2区 医学 Q1 ONCOLOGY
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
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引用次数: 0

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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来源期刊
CiteScore
11.20
自引率
1.80%
发文量
331
审稿时长
3 months
期刊介绍: Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
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