Modulating splicing with small molecular inhibitors of the spliceosome.
Modulating splicing with small molecular inhibitors of the spliceosome.
复制标题
用剪接体的小分子抑制剂调节剪接。
DOI：
10.1002/wrna.1381
复制
发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Jurica MS
中科院分区：
文献类型：
--
作者：
Effenberger KA;Urabe VK;Jurica MS
Small molecule inhibitors that target components of the spliceosome have great potential as tools to probe splicing mechanism and to dissect the splicing regulatory networks in cells. These compounds also hold promise as drug leads for diseases in which splicing regulation plays a critical role, including many cancers. Because the spliceosome is a complicated and dynamic macromolecular machine comprised of many RNA and protein components, a variety of compounds that interfere with different aspects of spliceosome assembly is needed to probe its function. By screening chemical libraries with high-throughput splicing assays, several labs have added to the collection of splicing inhibitors, although the mechanistic insight into splicing yielded from the initial compound hits is somewhat limited so far. In contrast, SF3B1 inhibitors stand out as a great example of what can be accomplished with small molecule tools. This group of compounds were first discovered as natural products that are cytotoxic to cancer cells, and then later shown to target the core spliceosome protein SF3B1. The inhibitors have since been used to uncover details of SF3B1 mechanism in the spliceosome and its impact on gene expression in cells. Continuing structure activity relationship analysis of the compounds is also making progress in identifying chemical features key to their function, which is critical to understanding the mechanism of SF3B1 inhibition. The knowledge is also key for the design of analogs with new and useful features for both splicing researchers and clinicians hoping to exploit splicing as pressure point to target in cancer therapy.
