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Marine Drugs
Volume 23
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10.3390/md23070289
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Article

The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells

by
Shijie Bi
1,†,
Yating Cao
1,†,
Shiyuan Fang
1,
Yanyan Chu
1,2,
Zixuan Zhang
1,
Meng Li
1,
Rilei Yu
1,
Jinbo Yang
1,2,
Yu Tang
1,2,* and
Peiju Qiu
1,2,*
1
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Rd, Qingdao 266003, China
2
Marine Biomedical Research Institute of Qiangdao, 23 Hongkong East Rd, Qingdao 266003, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Mar. Drugs 2025, 23(7), 289; https://doi.org/10.3390/md23070289
Submission received: 9 June 2025 / Revised: 8 July 2025 / Accepted: 10 July 2025 / Published: 16 July 2025
(This article belongs to the Special Issue Marine Bioactive Agents with Anticancer Potential: Discovery and Molecular Mechanisms)
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Abstract

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 5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that 5-3 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 5-3 depends highly on FLT3-ITD expression. Mechanically, 5-3 significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound 5-3 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 5-3 might be a drug candidate for the treatment of FLT3-ITD-positive AML.
Keywords: acute myeloid leukemia; FLT3-ITD mutation; diketopiperazine; tubulin acute myeloid leukemia; FLT3-ITD mutation; diketopiperazine; tubulin
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MDPI and ACS Style

Bi, S.; Cao, Y.; Fang, S.; Chu, Y.; Zhang, Z.; Li, M.; Yu, R.; Yang, J.; Tang, Y.; Qiu, P. The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells. Mar. Drugs 2025, 23, 289. https://doi.org/10.3390/md23070289

AMA Style

Bi S, Cao Y, Fang S, Chu Y, Zhang Z, Li M, Yu R, Yang J, Tang Y, Qiu P. The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells. Marine Drugs. 2025; 23(7):289. https://doi.org/10.3390/md23070289

Chicago/Turabian Style

Bi, Shijie, Yating Cao, Shiyuan Fang, Yanyan Chu, Zixuan Zhang, Meng Li, Rilei Yu, Jinbo Yang, Yu Tang, and Peiju Qiu. 2025. "The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells" Marine Drugs 23, no. 7: 289. https://doi.org/10.3390/md23070289

APA Style

Bi, S., Cao, Y., Fang, S., Chu, Y., Zhang, Z., Li, M., Yu, R., Yang, J., Tang, Y., & Qiu, P. (2025). The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells. Marine Drugs, 23(7), 289. https://doi.org/10.3390/md23070289

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