دورية أكاديمية
An MDM2 degrader shows potent cytotoxicity to MDM2-overexpressing acute lymphoblastic leukemia cells with minimal toxicity to normal cells/tissues.
| العنوان: | An MDM2 degrader shows potent cytotoxicity to MDM2-overexpressing acute lymphoblastic leukemia cells with minimal toxicity to normal cells/tissues. |
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| المؤلفون: | Liu T; Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, USA., Gu L; Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, USA., Mui A; Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, USA., Wu Z; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA., Albadari N; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA., Li W; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. Electronic address: wli@uthsc.edu., Zhou M; Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, USA. Electronic address: mzhou@emory.edu. |
| المصدر: | Cancer letters [Cancer Lett] 2024 Aug 28; Vol. 598, pp. 217126. Date of Electronic Publication: 2024 Jul 23. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Limerick : Elsevier Science Ireland Original Publication: Amsterdam, Elsevier/North-Holland. |
| مواضيع طبية MeSH: | Proto-Oncogene Proteins c-mdm2*/metabolism , Proto-Oncogene Proteins c-mdm2*/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/metabolism , Apoptosis*/drug effects , Xenograft Model Antitumor Assays* , Mice, SCID* , Tumor Suppressor Protein p53*/metabolism , Tumor Suppressor Protein p53*/genetics, Humans ; Animals ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Proteolysis/drug effects ; X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; Dose-Response Relationship, Drug ; Mice ; Female ; Structure-Activity Relationship |
| مستخلص: | The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression through both p53-dependent and -independent pathways. Here, we report a novel small-molecule chemical compound (MX69-102) that we identified to induce MDM2 protein degradation, resulting in reactivation of p53, inhibition of XIAP, and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL) in vitro and in vivo. We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modifications of MX69 and selected analog MX69-102, showing increased MDM2-targeting activity. MX69-102 exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Acute lymphoblastic leukemia; MDM2 degradation; Small-molecule inhibitor |
| المشرفين على المادة: | EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) EC 2.3.2.27 (MDM2 protein, human) 0 (Tumor Suppressor Protein p53) 0 (Antineoplastic Agents) 0 (X-Linked Inhibitor of Apoptosis Protein) 0 (XIAP protein, human) 0 (TP53 protein, human) |
| تواريخ الأحداث: | Date Created: 20240725 Date Completed: 20240815 Latest Revision: 20240815 |
| رمز التحديث: | 20240816 |
| DOI: | 10.1016/j.canlet.2024.217126 |
| PMID: | 39053726 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1872-7980 |
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| DOI: | 10.1016/j.canlet.2024.217126 |