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Design, synthesis, and biological activity evaluation of novel HDAC3 selective inhibitors for combination with Venetoclax against acute myeloid leukemia.
Liu, Enqiang; Chen, Yuxin; Qin, Mengting; Yue, Kairui; Sun, Simin; Jiang, Yuqi; Li, Xiaoyang.
Afiliación
  • Liu E; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • Chen Y; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • Qin M; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • Yue K; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • Sun S; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • Jiang Y; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China.
  • Li X; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China. Electronic address: lixiaoyang@ouc.edu.cn.
Eur J Med Chem ; 276: 116663, 2024 Oct 05.
Article en En | MEDLINE | ID: mdl-39047608
ABSTRACT
Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3. In this work, we improved the HDAC3 isotype selectivity of 13a, and obtained compound 9c through rational drug design. 9c shows a selectivity of 71 fold for HDAC3 over HDAC1 and can significantly inhibit the proliferation activity of MV4-11 cells in vitro. Furthermore, when combined with Venetoclax, 9c can effectively induce apoptosis in MV4-11 cells in vitro and reduce the expression of anti-apoptotic proteins, the development of HDAC3 selective inhibitors may serve as a potential lead compound to reverse Venetoclax resistance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Ensayos de Selección de Medicamentos Antitumorales / Diseño de Fármacos / Leucemia Mieloide Aguda / Apoptosis / Compuestos Bicíclicos Heterocíclicos con Puentes / Proliferación Celular / Inhibidores de Histona Desacetilasas / Histona Desacetilasas / Antineoplásicos Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Ensayos de Selección de Medicamentos Antitumorales / Diseño de Fármacos / Leucemia Mieloide Aguda / Apoptosis / Compuestos Bicíclicos Heterocíclicos con Puentes / Proliferación Celular / Inhibidores de Histona Desacetilasas / Histona Desacetilasas / Antineoplásicos Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Francia