Discovery of spiroindole-3,2′-pyrrolidin-2(1 H )-one based inhibitors targeting Brr2, a core component of the U5 snRNP

Masahiro Ito; Misa Iwatani; Takeshi YamamotoToshio TanakaTomohiro KawamotoDaisuke MorishitaAtsushi NakanishiHironobu Maezaki

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Discovery of spiroindole-3,2′-pyrrolidin-2(1 H )-one based inhibitors targeting Brr2, a core component of the U5 snRNP

机译：Discovery of spiroindole-3,2′-pyrrolidin-2(1 H )-one based inhibitors targeting Brr2, a core component of the U5 snRNP

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Graphical abstract Display Omitted Abstract Bad response to refrigeration 2 (Brr2) is a member of the Ski2-like RNA helicases, and an essential component of the U5 small nuclear ribonucleoprotein (snRNP). A particularly important role of Brr2 is the ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step in spliceosomal activation. Despite its biological importance, selective inhibitor for Brr2 had not been reported until our recent report. Here, we describe novel and structurally distinct spiroindole-3,2′-pyrrolidin-2(1 H )-one based Brr2 inhibitors with superior activity to the previously reported 4,6-dihydropyrido4,3- d pyrimidine-2,7(1 H ,3 H )-dione series. Using an RNA dependent ATPase assay as a guide, high-throughput screening, hit validation by structure–activity relationship (SAR) study, and subsequent chemical optimization to increase the ATPase inhibitory activity were performed. Thereafter, selectivity and helicase inhibitory activity of optimized compounds were confirmed. In the course of the study, compounds were synthesized using a three-component reaction, which accelerated the optimization process. All these efforts finally culminated in the discovery of the potent and selective Brr2 inhibitors ( 32a and 33a ) exhibiting helicase inhibitory activity at submicromolar concentrations. Thus, compounds 32a and 33a could be valuable molecular probes to study the functions of Brr2 and molecular machinery of RNA splicing. >

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《Bioorganic and medicinal chemistry》 |2017年第17期|4753-4767|共15页
作者
Masahiro Ito; Misa Iwatani; Takeshi YamamotoToshio TanakaTomohiro KawamotoDaisuke MorishitaAtsushi NakanishiHironobu Maezaki;
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Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited;

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正文语种英语
中图分类药学;
关键词
RNA helicase; Bad response to refrigeration 2 (Brr2); mRNA splicing; Small nuclear ribonucleoproteins (snRNPs); RNA dependent ATPase assay; Three-component reaction;

Discovery of spiroindole-3,2′-pyrrolidin-2(1 H )-one based inhibitors targeting Brr2, a core component of the U5 snRNP

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