4 years ago

Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2

Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2
Atsushi Nakanishi, Satoshi Endo, Masanori Miwa, Takeshi Yamamoto, Richard Tjhen, Tomohiro Kawamoto, Hironobu Maezaki, Misa Iwatani-Yoshihara, Toshio Tanaka, Kazuko Yonemori, Michael G. Klein, Daisuke Morishita, Ling Qin, Masahiro Ito
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00461

DOI: 10.1021/acs.jmedchem.7b00461

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