Design, Synthesis, and Biological Evaluation of Potent FLT3 Inhibitor for Acute Myeloid Leukemia (AML) Treatment

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2025-06-18 DOI:10.1002/ddr.70119

Kun Du, Yanan he, Jinyang Fu, Guimin Xue, Zhiqiang Zhang, Xiaokun Li, Yanle Zhi

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引用次数: 0

Abstract

Acute myeloid leukemia (AML) is a clonal malignant proliferative disease of myeloid progenitor cells in the hematopoietic system, with a lower than 5-year overall survival rate. At present, three FLT3 inhibitors have been approved, but these drugs are prone to cause resistance after a period of medication. Developing new FLT3 inhibitors with novel structures is an effective strategy to enhance drug treatment efficacy. This study presents an extension of our effort to design and synthesize a series of novel pyrimidine-2,4-diamine derivatives as inhibitors of FLT3. The most active compound, 7r, showed significant inhibition against FLT3 with IC₅₀ value of 7.82 nM. In addition, 7r exhibited prominent anticancer activities against AML cell lines, such as MV4-11 (IC₅₀ = 46.07 nM) and MOLM-13 (IC₅₀ = 51.6 nM). Compound 7r inhibited phosphorylation of FLT3 pathways in a dose-dependent manner in MV4-11 cell lines.

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有效FLT3抑制剂治疗急性髓性白血病（AML）的设计、合成和生物学评价

急性髓系白血病（Acute myeloid leukemia， AML）是一种造血系统中髓系祖细胞的克隆性恶性增生性疾病，总生存率低于5年。目前已有3种FLT3抑制剂获批，但这些药物在用药一段时间后容易产生耐药性。开发结构新颖的FLT3抑制剂是提高药物治疗效果的有效策略。本研究是我们设计和合成一系列新型嘧啶-2,4-二胺衍生物作为FLT3抑制剂的延伸。活性最强的化合物7r对FLT3有显著抑制作用，IC50值为7.82 nM。此外，7r对AML细胞系MV4-11 （IC50 = 46.07 nM）和MOLM-13 （IC50 = 51.6 nM）表现出明显的抗癌活性。在MV4-11细胞系中，化合物7r以剂量依赖性的方式抑制FLT3通路的磷酸化。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.