The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells
The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-canc...
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2025-07-01
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| author | Shijie Bi Yating Cao Shiyuan Fang Yanyan Chu Zixuan Zhang Meng Li Rilei Yu Jinbo Yang Yu Tang Peiju Qiu |
| author_facet | Shijie Bi Yating Cao Shiyuan Fang Yanyan Chu Zixuan Zhang Meng Li Rilei Yu Jinbo Yang Yu Tang Peiju Qiu |
| author_sort | Shijie Bi |
| collection | DOAJ |
| description | The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely <b>5-3</b>, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that <b>5-3</b> potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of <b>5-3</b> depends highly on FLT3-ITD expression. Mechanically, <b>5-3</b> significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound <b>5-3</b> is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that <b>5-3</b> might be a drug candidate for the treatment of FLT3-ITD-positive AML. |
| format | Article |
| id | doaj-art-dcfc9fd6c4774f3ca68670fef2ee8b01 |
| institution | DOAJ |
| issn | 1660-3397 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Marine Drugs |
| spelling | doaj-art-dcfc9fd6c4774f3ca68670fef2ee8b012025-08-20T02:45:56ZengMDPI AGMarine Drugs1660-33972025-07-0123728910.3390/md23070289The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) CellsShijie Bi0Yating Cao1Shiyuan Fang2Yanyan Chu3Zixuan Zhang4Meng Li5Rilei Yu6Jinbo Yang7Yu Tang8Peiju Qiu9Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, ChinaThe internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely <b>5-3</b>, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that <b>5-3</b> potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of <b>5-3</b> depends highly on FLT3-ITD expression. Mechanically, <b>5-3</b> significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound <b>5-3</b> is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that <b>5-3</b> might be a drug candidate for the treatment of FLT3-ITD-positive AML.https://www.mdpi.com/1660-3397/23/7/289acute myeloid leukemiaFLT3-ITD mutationdiketopiperazinetubulin |
| spellingShingle | Shijie Bi Yating Cao Shiyuan Fang Yanyan Chu Zixuan Zhang Meng Li Rilei Yu Jinbo Yang Yu Tang Peiju Qiu The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells Marine Drugs acute myeloid leukemia FLT3-ITD mutation diketopiperazine tubulin |
| title | The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells |
| title_full | The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells |
| title_fullStr | The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells |
| title_full_unstemmed | The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells |
| title_short | The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells |
| title_sort | novel diketopiperazine derivative compound 5 3 selectively inhibited the proliferation of flt3 itd mutant acute myeloid leukemia aml cells |
| topic | acute myeloid leukemia FLT3-ITD mutation diketopiperazine tubulin |
| url | https://www.mdpi.com/1660-3397/23/7/289 |
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