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1,3,5-三嗪在具有良好药代动力学的患者来源原位异种移植小鼠模型中抑制骨肉瘤并防止肺转移。

1,3,5-triazines inhibit osteosarcoma and avert lung metastasis in a patient-derived orthotopic xenograft mouse model with favorable pharmacokinetics.

作者信息

Su Qing, Xu Baolin, Tian Zhoubin, Gong Ziling

机构信息

Department of Orthopedic Oncology, Yantai Shan Hospital, Yantai, 264003, China.

Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310006, China.

出版信息

Iran J Basic Med Sci. 2022 Mar;25(3):295-301. doi: 10.22038/IJBMS.2022.62705.13873.

DOI:10.22038/IJBMS.2022.62705.13873
PMID:35656180
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9148403/
Abstract

OBJECTIVES

Osteosarcoma is a major solid malignant tumor of bone, possessing significant burden on healthcare due to non-availability of specific anticancer agents. The current study was conducted to identify novel 1,3,5-triazine derivatives against osteosarcoma.

MATERIALS AND METHODS

The compounds were synthesized in a straight-forward two-step reaction and subsequently tested against PI3K and mTOR kinase and anticancer activity against osteosarcoma cells (MG-63, U2-OS, and Saos-2). The effect of the most potent compound was evaluated on apoptosis and cell phase of Saos-2 cells. The pharmacological activity was further established in the patient-derived orthotopic xenograft (PDOX) mouse model.

RESULTS

The developed compounds 8 (a-f) showed significant inhibitory activities against PI3K, mTOR, and OS cells. Among the tested series, compound showed highly potent PI3K/mTOR inhibitory activity with significant anticancer activity against Saos-2 cells compared with Imatinib as standard. It also induces apoptosis and causes G2/M arrest in Saos-2 cells. Compound significantly improved body weight, reduced tumor volume, and inhibited lung metastasis in athymic nude mice in a PDOX mouse model. It also showed optimal pharmacokinetic parameters in SD rats.

CONCLUSION

In summary, 1,3,5-triazine analogs were identified as new PI3K/mTOR inhibitors against osteosarcoma.

摘要

目的

骨肉瘤是一种主要的骨实体恶性肿瘤，由于缺乏特异性抗癌药物，给医疗保健带来了巨大负担。本研究旨在鉴定针对骨肉瘤的新型1,3,5 - 三嗪衍生物。

材料与方法

通过简单的两步反应合成化合物，随后针对PI3K和mTOR激酶进行测试，并检测其对骨肉瘤细胞（MG - 63、U2 - OS和Saos - 2）的抗癌活性。评估最有效化合物对Saos - 2细胞凋亡和细胞周期的影响。在患者来源的原位异种移植（PDOX）小鼠模型中进一步确定其药理活性。

结果

所开发的化合物8（a - f）对PI3K、mTOR和骨肉瘤细胞显示出显著的抑制活性。在测试系列中，与作为标准对照的伊马替尼相比，化合物 显示出高效的PI3K/mTOR抑制活性以及对Saos - 2细胞的显著抗癌活性。它还能诱导Saos - 2细胞凋亡并导致G2/M期阻滞。在PDOX小鼠模型中，化合物 显著改善了无胸腺裸鼠的体重，减小了肿瘤体积，并抑制了肺转移。在SD大鼠中它还显示出最佳的药代动力学参数。

结论

总之，1,3,5 - 三嗪类似物被鉴定为针对骨肉瘤的新型PI3K/mTOR抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/4678c28ea460/IJBMS-25-295-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/b316259ead5d/IJBMS-25-295-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/3604de0a4b29/IJBMS-25-295-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/9adec7a88266/IJBMS-25-295-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/574ce4e9b5e0/IJBMS-25-295-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/4678c28ea460/IJBMS-25-295-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/b316259ead5d/IJBMS-25-295-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/3604de0a4b29/IJBMS-25-295-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/9adec7a88266/IJBMS-25-295-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/574ce4e9b5e0/IJBMS-25-295-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a2/9148403/4678c28ea460/IJBMS-25-295-g005.jpg

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