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DNA-Encoded Library Screening To Inform Design of a Ribonuclease Targeting Chimera (RiboTAC).


ABSTRACT: 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.

SUBMITTER: Meyer SM 

PROVIDER: S-EPMC10786349 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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DNA-Encoded Library Screening To Inform Design of a Ribonuclease Targeting Chimera (RiboTAC).

Meyer Samantha M SM   Tanaka Toru T   Zanon Patrick R A PRA   Baisden Jared T JT   Abegg Daniel D   Yang Xueyi X   Akahori Yoshihiro Y   Alshakarchi Zainab Z   Cameron Michael D MD   Adibekian Alexander A   Disney Matthew D MD  

Journal of the American Chemical Society 20221107 46


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-as  ...[more]

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