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Proteolysis-Targeting Chimera (PROTAC) Modification of Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive Acute Myeloid Leukemia Cells.
Cao, Sheng; Ma, Lan; Liu, Yulin; Wei, Mingming; Yao, Yuhong; Li, Chen; Wang, Ruonan; Liu, Ning; Dong, Zhiqiang; Li, Xuechun; Li, Ming; Wang, Xiaoji; Yang, Cheng; Yang, Guang.
Afiliación
  • Cao S; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Ma L; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Liu Y; Tianjin International Joint Academy of Biomedicine, Tianjin 300457, P. R. China.
  • Wei M; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Yao Y; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Li C; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Wang R; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Liu N; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Dong Z; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Li X; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Li M; Tianjin International Joint Academy of Biomedicine, Tianjin 300457, P. R. China.
  • Wang X; The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
  • Yang C; Tianjin International Joint Academy of Biomedicine, Tianjin 300457, P. R. China.
  • Yang G; Cangzhou Institutes for Food and Drug Control, Cangzhou 061000, P. R. China.
J Med Chem ; 64(22): 16497-16511, 2021 11 25.
Article en En | MEDLINE | ID: mdl-34694800
Acute myeloid leukemia (AML) refers to one of the most lethal blood malignancies worldwide. FLT3-ITD mutation is recognized as the most common one that predicted a poorer prognosis. There have been many prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies. However, as impacted by undesirable off-target effects, differentiated metabolic issues, and clinical drug resistance problems, it remains challenging to discover alternative and promising solutions for treating FLT3-ITD+ AML. In this study, dovitinib was chemically modified and converted into CRBN-recruiting PROTACs. Two active compounds were identified, which showed enhanced antiproliferative effects against FLT3-ITD+ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin-proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD+ AML.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bencimidazoles / Leucemia Mieloide Aguda / Quinolonas / Tirosina Quinasa 3 Similar a fms / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bencimidazoles / Leucemia Mieloide Aguda / Quinolonas / Tirosina Quinasa 3 Similar a fms / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos