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- Title
Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors.
- Authors
Kim, Hyo Jeong; Ryu, Hwani; Song, Jie-Young; Hwang, Sang-Gu; Jalde, Shivakumar S.; Choi, Hyun-Kyung; Ahn, Jiyeon
- Abstract
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.
- Subjects
POLY ADP ribose; ACUTE myeloid leukemia; DASATINIB; DNA repair; IMIDAZOPYRIDINES; POLY(ADP-ribose) polymerase; PROTEIN-tyrosine kinases; DNA damage
- Publication
Molecules, 2020, Vol 25, Issue 21, p5154
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25215154