Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 46, Pages 21096-21102Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c07217
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Funding
- National Institutes of Health [R01 CA249180, R35 NS116846, R01 GM145886, S10OD021550]
- Scheller Graduate Student Fellowship
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This study utilized a DNA-encoded library to identify a compound that activates ribonuclease activity and incorporated it into the design of a next-generation ribonuclease targeting chimera. The developed chimera successfully alleviated the cellular phenotype of triple-negative breast cancer cells. This work demonstrates the potential of DNA-encoded libraries in identifying compounds with effector functions in heterobifunctional compounds.
Ribonuclease targeting chimeras (RiboTACs) induce degradation of an RNA target by facilitating an interaction between an RNA and a ribonuclease (RNase). We describe the screening of a DNA-encoded library (DEL) to identify binders of monomeric RNase L to provide a compound that induced dimerization of RNase L, activating its ribonuclease activity. This compound was incorporated into the design of a next-generation RiboTAC that targeted the microRNA-21 (miR-21) precursor and alleviated a miR-21-associated cellular phenotype in triple-negative breast cancer cells. The RNA-binding module in the RiboTAC is Dovitinib, a known receptor tyrosine kinase (RTK) inhibitor, which was previously identified to bind miR-21 as an off-target. Conversion of Dovitinib into this RiboTAC reprograms the known drug to selectively affect the RNA target. This work demonstrates that DEL can be used to identify compounds that bind and recruit proteins with effector functions in heterobifunctional compounds.
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