دورية أكاديمية
Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.
| العنوان: | Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML. |
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| المؤلفون: | Wu M; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: wmfayd@163.com., Wang W; Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences; Zhejiang University, Cancer Center; Zhejiang University School of Medicine Children'sHospital, Division of Hematology-Oncology, Hangzhou, 310058, PR China., Mao X; Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences; Zhejiang University, Cancer Center; Zhejiang University School of Medicine Children'sHospital, Division of Hematology-Oncology, Hangzhou, 310058, PR China., Wu Y; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China., Jin Y; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China., Liu T; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China., Lu Y; Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, PR China., Dai H; Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, PR China., Zeng S; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China., Huang W; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China., Wang Y; College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China., Yao X; Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macau, 999078, PR China., Che J; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: chejx@zju.edu.cn., Ying M; Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences; Zhejiang University, Cancer Center; Zhejiang University School of Medicine Children'sHospital, Division of Hematology-Oncology, Hangzhou, 310058, PR China. Electronic address: mying@zju.edu.cn., Dong X; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, PR China. Electronic address: dongxw@zju.edu.cn. |
| المصدر: | European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116539. Date of Electronic Publication: 2024 May 31. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| مواضيع طبية MeSH: | Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/chemical synthesis , Cyclin-Dependent Kinases*/antagonists & inhibitors , Cyclin-Dependent Kinases*/metabolism , Drug Discovery* , fms-Like Tyrosine Kinase 3*/antagonists & inhibitors , fms-Like Tyrosine Kinase 3*/metabolism , Leukemia, Myeloid, Acute*/drug therapy , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Protein Kinase Inhibitors*/chemical synthesis , Proteolysis Targeting Chimera*/chemistry , Proteolysis Targeting Chimera*/pharmacology , Proteolysis Targeting Chimera*/therapeutic use , Proteolysis*, Humans ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Molecular Structure ; Structure-Activity Relationship |
| مستخلص: | AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC 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 Elsevier Masson SAS. All rights reserved.) |
| فهرسة مساهمة: | Keywords: AML; CDKs; Differentiation therapy; FLT3; PROTACs; Proliferation inhibition |
| المشرفين على المادة: | 0 (Antineoplastic Agents) EC 2.7.11.22 (Cyclin-Dependent Kinases) EC 2.7.10.1 (FLT3 protein, human) EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) 0 (Protein Kinase Inhibitors) 0 (Proteolysis Targeting Chimera) |
| تواريخ الأحداث: | Date Created: 20240615 Date Completed: 20240710 Latest Revision: 20240711 |
| رمز التحديث: | 20240711 |
| DOI: | 10.1016/j.ejmech.2024.116539 |
| PMID: | 38878515 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1768-3254 |
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| DOI: | 10.1016/j.ejmech.2024.116539 |