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Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD(+) induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 in...

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Detalles Bibliográficos
Autores principales: Kim, Hyo Jeong, Ryu, Hwani, Song, Jie-Young, Hwang, Sang-Gu, Jalde, Shivakumar S., Choi, Hyun-Kyung, Ahn, Jiyeon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663913/
https://www.ncbi.nlm.nih.gov/pubmed/33167505
http://dx.doi.org/10.3390/molecules25215154
Descripción
Sumario:Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD(+) induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD(+) AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.