A potent dual inhibitor targeting COX-2 and HDAC of acute myeloid leukemia cells.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-10-31 DOI:10.1007/s11030-024-11000-w

Xiang Qin, Xueting Wang, Chunmei Yang, Fan Wang, Tingting Fang, Didi Gu, Qulian Guo, Qiuyu Meng, Wenjun Liu, Lu Yang

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引用次数: 0

Abstract

Acute myeloid leukemia (AML) is an aggressive cancer with complex issues of drug resistance and a poor prognosis; thus, effective therapeutics is urgently needed for AML. In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

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一种针对急性髓性白血病细胞 COX-2 和 HDAC 的强效双重抑制剂。

急性髓性白血病（AML）是一种侵袭性癌症，具有复杂的耐药性问题，预后较差；因此，AML急需有效的治疗方法。在这项研究中，我们设计并合成了环氧化酶-2（COX-2）和组蛋白去乙酰化酶（HDAC）双重抑制剂 IMC-HA 和 IMC-OPD，并将其应用于治疗 AML。IMC-HA由吲哚美辛（IMC）的COX-2抑制剂骨架和羟氨基的HDAC抑制剂分子组成，对AML细胞（THP-1和U937）具有强效的抗增殖活性，而对正常细胞的细胞毒性较低。分子对接模拟表明，IMC-HA 与 HDAC 和 COX-2 具有很高的结合亲和力，结合能分别为 -6.8 和 -9.0 kcal/mol。机理研究发现，IMC-HA能诱导急性髓细胞凋亡和G0/G1期停滞，其特征是凋亡蛋白和细胞周期相关蛋白的表达发生了改变。进一步的研究表明，IMC-HA 还能抑制 AML 细胞中的 MEK/ERK 信号通路。总之，我们认为 IMC-HA 可以作为一种强效的 COX-2/HDAC 双抑制剂，改善急性髓细胞白血病的治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;