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Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00461
Misa Iwatani-Yoshihara , Masahiro Ito , Michael G. Klein 1 , Takeshi Yamamoto , Kazuko Yonemori , Toshio Tanaka , Masanori Miwa , Daisuke Morishita , Satoshi Endo , Richard Tjhen 1 , Ling Qin 1 , Atsushi Nakanishi , Hironobu Maezaki , Tomohiro Kawamoto
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00461
Misa Iwatani-Yoshihara , Masahiro Ito , Michael G. Klein 1 , Takeshi Yamamoto , Kazuko Yonemori , Toshio Tanaka , Masanori Miwa , Daisuke Morishita , Satoshi Endo , Richard Tjhen 1 , Ling Qin 1 , Atsushi Nakanishi , Hironobu Maezaki , Tomohiro Kawamoto
Affiliation
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Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds to an unexpected allosteric site between the C-terminal and the N-terminal helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9 with helicase inhibitory activity. Our findings demonstrate an effective strategy to explore selective inhibitors for helicases, and 9 could be a promising starting point for exploring molecular probes to elucidate biological functions and the therapeutic relevance of Brr2.
中文翻译：
发现针对剪接体RNA解旋酶Brr2的变构抑制剂
Brr2是属于Ski2样亚家族的RNA解旋酶，是剪接体的重要组成部分。Brr2催化U4 / U6 RNA双链体的ATP依赖性解链，这是剪接体激活的关键步骤。使用RNA依赖的ATPase测定和最初的SAR研究开展的HTS运动确定了两种不同的Brr2抑制剂3和12。共晶体结构揭示了3个绑定到C末端和N末端解旋酶盒之间的意外变构位点，而12个结合了N末端盒内的RNA结合位点。选择性分析表明，变构抑制剂3比RNA位点结合剂12更具有Brr2选择性。化学优化图3使用SBDD最终发现了具有解旋酶抑制活性的有效且选择性的Brr2抑制剂9。我们的发现证明了探索解旋酶选择性抑制剂的有效策略，并且9可能是探索分子探针以阐明Brr2的生物学功能和治疗相关性的有希望的起点。
更新日期：2017-06-28
中文翻译：
发现针对剪接体RNA解旋酶Brr2的变构抑制剂
Brr2是属于Ski2样亚家族的RNA解旋酶，是剪接体的重要组成部分。Brr2催化U4 / U6 RNA双链体的ATP依赖性解链，这是剪接体激活的关键步骤。使用RNA依赖的ATPase测定和最初的SAR研究开展的HTS运动确定了两种不同的Brr2抑制剂3和12。共晶体结构揭示了3个绑定到C末端和N末端解旋酶盒之间的意外变构位点，而12个结合了N末端盒内的RNA结合位点。选择性分析表明，变构抑制剂3比RNA位点结合剂12更具有Brr2选择性。化学优化图3使用SBDD最终发现了具有解旋酶抑制活性的有效且选择性的Brr2抑制剂9。我们的发现证明了探索解旋酶选择性抑制剂的有效策略，并且9可能是探索分子探针以阐明Brr2的生物学功能和治疗相关性的有希望的起点。
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