Synthesis and Biological Evaluation of MEK/mTOR Multifunctional Inhibitors as Novel Anticancer Agents.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-05-16 DOI:10.1021/acs.jmedchem.5c00376

Marcian E Van Dort,Lucas McDonald,Youngsoon Jang,Kevin Heist,Christopher A Bonham,Kamryn Abraskin,Thomas L Chenevert,Brian D Ross

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引用次数: 0

Abstract

The mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) signaling nodes play a crucial role in many human cancers. Due to the molecular reciprocity between MAPK and mTOR signaling nodes, development of compounds with multikinase targeting was explored. A series of mTOR inhibitor analogs of AZD8055 and AZD2014 were designed to allow for covalent linking to a potent MAPK kinase (MEK) inhibitor to produce a single, bivalent chemical entity. Dual-acting agents (i.e., compound LP-65) were synthesized displaying high in vitro inhibition of both MEK (IC50 = 83.2 nM) and mTOR (IC50 = 40.5 nM). Additionally, compound LP-65 demonstrated significant modulation of MEK and mTOR signaling activity in human glioma cells (D54) and human melanoma cells (A375), with a corresponding decrease in cellular proliferation and migration. Treatment of mice with LP-65 (40 mg/kg) having a myeloproliferative neoplasm, myelofibrosis, revealed down modulation of in vivo signaling pathways and therapeutic efficacy.

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新型抗癌药物MEK/mTOR多功能抑制剂的合成及生物学评价

丝裂原活化蛋白激酶（MAPK）和雷帕霉素的机制靶点（mTOR）信号节点在许多人类癌症中起着至关重要的作用。由于MAPK和mTOR信号节点之间的分子互反性，研究人员探索了多激酶靶向化合物的开发。设计了一系列mTOR抑制剂类似物AZD8055和AZD2014，允许与有效的MAPK激酶（MEK）抑制剂共价连接，以产生单一的二价化学实体。合成双作用药物（即化合物LP-65），对MEK （IC50 = 83.2 nM）和mTOR （IC50 = 40.5 nM）均有较高的体外抑制作用。此外，化合物LP-65在人胶质瘤细胞（D54）和人黑色素瘤细胞（A375）中显示出显著的MEK和mTOR信号活性调节，并相应降低细胞增殖和迁移。用LP-65 （40 mg/kg）治疗骨髓增生性肿瘤、骨髓纤维化小鼠，显示出下调体内信号通路和治疗效果。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.