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

  • Molecules. 2020 Nov 5;25(21):5154. doi: 10.3390/molecules25215154.
Hyo Jeong Kim  1 ,  Hwani Ryu  1  2 ,  Jie-Young Song  1 ,  Sang-Gu Hwang  1 ,  Shivakumar S Jalde  3 ,  Hyun-Kyung Choi  3 ,  Jiyeon Ahn  1
Affiliations
  • 1. Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
  • 2. Department of Biology, Korea University, Seoul 02841, Korea.
  • 3. Department of Medicinal Chemistry, Jungwon University, Goesan 28024, Korea.
PMID: 33167505 DOI: 10.3390/molecules25215154
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.

Keywords
DNA damage repair; FLT3 inhibitor; PARP1 inhibitor; acute myeloid leukemia; combination therapy.
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