Abstract：
:Small-molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind to and cleave RNA in a selective and substoichiometric manner. Here, we investigate the ability of RNA-targeted degradation to improve the selectivity of small molecules targeting RNA. The microRNA-210 hairpin precursor (pre-miR-210) is overexpressed in hypoxic cancers. Previously, a small molecule (Targapremir-210 [TGP-210]) targeted this RNA in cells, but with a 5-fold window for DNA binding. Appendage of a nuclease recruitment module onto TGP-210 locally recruited ribonuclease L onto pre-miR-210, triggering its degradation. The chimera has enhanced selectivity compared with TGP-210 with nanomolar binding to the pre-miR-210, but no DNA binding, and is broadly selective for affecting RNA function in cells. Importantly, it cleaved pre-miR-210 substoichiometrically and induced apoptosis in breast cancer cells.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Costales MG,Suresh B,Vishnu K,Disney MDdoi
10.1016/j.chembiol.2019.04.008subject
Has Abstractpub_date
2019-08-15 00:00:00pages
1180-1186.e5issue
8eissn
2451-9456issn
2451-9448pii
S2451-9456(19)30122-9journal_volume
26pub_type
杂志文章abstract：:Disorders of bone healing and remodeling are indications with an unmet need for effective pharmacological modulators. We used a high-throughput screen to identify activators of the bone marker alkaline phosphatase (ALP), and discovered 6,8-dimethyl-3-(4-phenyl-1H-imidazol-5-yl)quinolin-2(1H)-one (DIPQUO). DIPQUO marke...
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journal_title：Cell chemical biology
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journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.05.010
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