MMP13 as an effective target of an active trifluoromethyl quinazoline compound against osteosarcoma.

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY Toxicology and applied pharmacology Pub Date : 2024-12-12 DOI:10.1016/j.taap.2024.117204

Chang-Hua Zhou, Ting Zhang, Jia Yu, Gang Yu, Sha Cheng, Hui Wu, Bi-Xue Xu, Heng Luo, Xiao-Bin Tian

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Abstract

Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.

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MMP13 是一种活性三氟甲基喹唑啉化合物对抗骨肉瘤的有效靶点。

骨肉瘤（Osteosarcoma， OS）是一种高度致命的恶性肿瘤，转移率高，预后差。基质金属蛋白酶-13 （MMP13）参与肿瘤转移。其表达增加与远处转移及预后不良密切相关。设计合成了三氟甲基喹唑啉化合物KZL-201，并研究了其对OS细胞生长的抑制作用。本研究旨在结合生物信息学、分子生物学、细胞学和动物学等方法探讨KZL-201在OS中的作用机制。体外实验表明，KZL-201能抑制OS细胞的增殖、侵袭和迁移；KZL-201诱导细胞凋亡，使细胞周期停留在G2/M期。分子对接、细胞热移实验和基因沉默实验结果表明，KZL-201与MMP13具有较强的亲和力。KZL-201通过调控TGF-β1/Smad2/3通路抑制143B细胞的进展。因此，MMP13是KZL-201抑制143B细胞进展的重要靶基因。体内实验表明，KZL-201能够抑制OS组织的生长和MMP13在OS组织中的表达。综上所述，KZL-201靶向MMP13并抑制其表达，从而通过调控TGF-β1/Smad2/3通路抑制OS的进展。

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产品信息

索莱宝

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)

来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.