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<sup>+</sup> induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we ide...
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MDPI AG
2020-11-01
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| Online Access: | https://www.mdpi.com/1420-3049/25/21/5154 |
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| author | Hyo Jeong Kim Hwani Ryu Jie-Young Song Sang-Gu Hwang Shivakumar S. Jalde Hyun-Kyung Choi Jiyeon Ahn |
| author_facet | Hyo Jeong Kim Hwani Ryu Jie-Young Song Sang-Gu Hwang Shivakumar S. Jalde Hyun-Kyung Choi Jiyeon Ahn |
| author_sort | Hyo Jeong Kim |
| collection | DOAJ |
| description | 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 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<sup>+</sup> AML cells, increasing apoptosis. The anti-leukemic activity of <b>7c</b> was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, <b>7c</b> suppressed the expression of DNA damage repair genes. Combination treatment with <b>7c</b> and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that <b>7c</b> is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with <b>7c</b> and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML. |
| first_indexed | 2024-03-10T15:04:35Z |
| format | Article |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:04:35Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-eb5e6fcebe7d4a8f9413399b1a71ca1e2023-11-20T19:55:05ZengMDPI AGMolecules1420-30492020-11-012521515410.3390/molecules25215154Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 InhibitorsHyo Jeong Kim0Hwani Ryu1Jie-Young Song2Sang-Gu Hwang3Shivakumar S. Jalde4Hyun-Kyung Choi5Jiyeon Ahn6Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDepartment of Medicinal Chemistry, Jungwon University, Goesan 28024, KoreaDepartment of Medicinal Chemistry, Jungwon University, Goesan 28024, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaInternal 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 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<sup>+</sup> AML cells, increasing apoptosis. The anti-leukemic activity of <b>7c</b> was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, <b>7c</b> suppressed the expression of DNA damage repair genes. Combination treatment with <b>7c</b> and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that <b>7c</b> is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with <b>7c</b> and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.https://www.mdpi.com/1420-3049/25/21/5154FLT3 inhibitoracute myeloid leukemiaDNA damage repaircombination therapyPARP1 inhibitor |
| spellingShingle | Hyo Jeong Kim Hwani Ryu Jie-Young Song Sang-Gu Hwang Shivakumar S. Jalde Hyun-Kyung Choi Jiyeon Ahn Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors Molecules FLT3 inhibitor acute myeloid leukemia DNA damage repair combination therapy PARP1 inhibitor |
| title | Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors |
| title_full | Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors |
| title_fullStr | Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors |
| title_full_unstemmed | Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors |
| title_short | Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors |
| title_sort | discovery of oxazol 2 amine derivatives as potent novel flt3 inhibitors |
| topic | FLT3 inhibitor acute myeloid leukemia DNA damage repair combination therapy PARP1 inhibitor |
| url | https://www.mdpi.com/1420-3049/25/21/5154 |
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