Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.
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Anlotinib enhances the pro-apoptotic effect of APG-115 on acute myeloid leukemia cell lines by inhibiting the P13K/AKT signaling pathway.
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December 2024
Department of Hematopathy, Henan Institute of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China. Electronic address:
Background: APG-115 is a novel small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells. Anlotinib inhibits tumor angiogenesis and promotes apoptosis. In this study, we investigated the apoptotic effect and potential mechanism of APG-115 and anlotinib combination on AML cell lines with different p53 backgrounds.
View Article and Find Full Text PDFKT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors.
Mol Cancer Ther
December 2024
Kymera Therapeutics, Inc., Watertown, Massachusetts, United States.
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.
View Article and Find Full Text PDFAn update patent review of MDM2-p53 interaction inhibitors (2019-2023).
Expert Opin Ther Pat
December 2024
Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Lodz, Poland.
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- The p53 tumor suppressor protein is commonly disrupted in cancers through TP53 mutations or MDM2 overexpression, leading to interest in inhibitors that can release p53 for cancer therapy.
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- PPM1D is a phosphatase linked to cancer that negatively regulates the DNA damage response and p53, and its inhibition can slow tumor growth and enhance the effectiveness of cancer treatments.
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Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction.
Eur J Med Chem
April 2024
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China. Electronic address:
Article Synopsis
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