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外显子跳跃筛选鉴定出了能够有效调节前体 mRNA 剪接的抗肿瘤药物，提示了新的治疗应用。

An exon skipping screen identifies antitumor drugs that are potent modulators of pre-mRNA splicing, suggesting new therapeutic applications.

机构信息

Bioscience Division, SRI International, Menlo Park, CA, United States of America.

Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, United States of America.

出版信息

PLoS One. 2020 May 29;15(5):e0233672. doi: 10.1371/journal.pone.0233672. eCollection 2020.

DOI:10.1371/journal.pone.0233672
PMID:32469945
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7259758/
Abstract

Agents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-562271) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further support the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for the discovery of new chemotherapeutic agents for a range of diseases.

摘要

调节前体 mRNA 剪接的药物在多个治疗领域都具有重要意义，包括癌症。我们报告了最近应用基于细胞的三重外显子跳跃萤光素酶报告基因（TESLR）进行的筛选结果，该报告基因使用的文库由 FDA 批准的药物、临床化合物和具有机制特征的工具化合物组成。确证性试验表明，三种临床抗肿瘤治疗候选药物（milciclib、PF-3758309 和 PF-562271）是有效的剪接调节剂，实际上它们是参与调控剪接体的多种激酶的纳摩尔抑制剂。我们还报告了新的 SF3B1 拮抗剂（sudemycinol C 和 E）的鉴定，并表明这些拮抗剂可用于开发 SF3B1 小分子配体的置换测定法。这些结果进一步支持了为治疗癌症和其他疾病而开发针对剪接体的药物的广泛潜力，以及为一系列疾病发现新化疗药物的新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/866e810ab2a2/pone.0233672.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/2d215c8e93f6/pone.0233672.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/e5f8176d56cf/pone.0233672.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/932694e4b9e0/pone.0233672.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/a4c62373bc77/pone.0233672.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/5bd534a237e0/pone.0233672.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/491895512b5f/pone.0233672.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/866e810ab2a2/pone.0233672.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/2d215c8e93f6/pone.0233672.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/e5f8176d56cf/pone.0233672.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/932694e4b9e0/pone.0233672.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/a4c62373bc77/pone.0233672.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/5bd534a237e0/pone.0233672.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/491895512b5f/pone.0233672.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6db6/7259758/866e810ab2a2/pone.0233672.g007.jpg

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