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

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.

SUBMITTER: Kim HJ 

PROVIDER: S-EPMC7663913 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Kim Hyo Jeong HJ   Ryu Hwani H   Song Jie-Young JY   Hwang Sang-Gu SG   Jalde Shivakumar S SS   Choi Hyun-Kyung HK   Ahn Jiyeon J  

Molecules (Basel, Switzerland) 20201105 21

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<sup>+</sup> 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)-<i>N</i>-phenyloxazol-2-amine (compound <b>7</b>; <b>7c</b>) as candidates for the treatment of AML. The results showed that <b>7c</b> inhibited t  ...[more]

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