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三环苯并[cd]氮杂卓类选择性抑制 Pim 激酶的活性，并限制 Epstein-Barr 病毒转化细胞的生长。

Tricyclic Benzo[cd]azulenes selectively inhibit activities of Pim kinases and restrict growth of Epstein-Barr virus-transformed cells.

机构信息

Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Finland.

出版信息

PLoS One. 2013;8(2):e55409. doi: 10.1371/journal.pone.0055409. Epub 2013 Feb 6.

DOI:10.1371/journal.pone.0055409
PMID:23405147
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3566155/
Abstract

Oncogenic Pim family kinases are often overexpressed in human hematopoietic malignancies as well as in solid tumours. These kinases contribute to tumorigenesis by promoting cell survival and by enhancing resistance against chemotherapy and radiation therapy. Furthermore, we have recently shown that they increase the metastatic potential of adherent cancer cells. Here we describe identification of tricyclic benzo[cd]azulenes and their derivatives as effective and selective inhibitors of Pim kinases. These compounds inhibit Pim autophosphorylation and abrogate the anti-apoptotic effects of Pim kinases. They also reduce cancer cell motility and suppress proliferation of lymphoblastoid cell lines infected and immortalized by the Epstein-Barr virus. Thus, these novel Pim-selective inhibitors provide promising compounds for both research and therapeutic purposes.

摘要

致癌性 Pim 家族激酶在人类造血恶性肿瘤以及实体瘤中常常过度表达。这些激酶通过促进细胞存活和增强对化疗和放疗的抵抗来促进肿瘤发生。此外，我们最近表明，它们增加了贴壁癌细胞的转移潜能。在这里，我们描述了三环苯并[cd]氮杂卓及其衍生物作为 Pim 激酶的有效和选择性抑制剂的鉴定。这些化合物抑制 Pim 自身磷酸化并消除 Pim 激酶的抗凋亡作用。它们还降低了受 Epstein-Barr 病毒感染和永生化的淋巴母细胞系的癌细胞迁移并抑制其增殖。因此，这些新型的 Pim 选择性抑制剂为研究和治疗目的提供了有前途的化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/ba2550c21f8c/pone.0055409.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/61de451c1405/pone.0055409.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/fb640e47b40b/pone.0055409.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/14005f5dcfd1/pone.0055409.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/50e1cde426a6/pone.0055409.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/ba2550c21f8c/pone.0055409.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/61de451c1405/pone.0055409.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/fb640e47b40b/pone.0055409.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/14005f5dcfd1/pone.0055409.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/50e1cde426a6/pone.0055409.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fed/3566155/ba2550c21f8c/pone.0055409.g005.jpg

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