Dual FLT3/TOPK inhibitor with activity against FLT3-ITD secondary mutations potently inhibits acute myeloid leukemia cell lines

AIM: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainl...

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Detalles Bibliográficos
Autores principales: Dayal, Neetu, Opoku-Temeng, Clement, Hernandez, Delmis E, Sooreshjani, Moloud Aflaki, Carter-Cooper, Brandon A, Lapidus, Rena G, Sintim, Herman O
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Future Science Ltd 2018
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367750/
https://www.ncbi.nlm.nih.gov/pubmed/29437468
http://dx.doi.org/10.4155/fmc-2017-0298
Descripción
Sumario:AIM: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691. RESULTS: HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines. HSD1169 was active against MV4–11 and Molm-14 (FLT3-ITD cell lines) but not NOMO-1 or HL60 (FLT3-WT cell lines). HSD1169 was also active against sorafenib-resistant Molm13-res cell line (containing FLT3-ITD/D835Y). CONCLUSION: HSD1169 or an analog could become a therapeutic agent for AML containing drug-resistant FLT3-ITD.

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