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

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Ribonuclease targeting chimeras (RiboTACs) harness RNases to degrade specific RNA targets.
• Developing targeted RNA degradation therapies requires identifying specific protein binders and recruiters.

Purpose of the Study:

• To identify compounds that bind and induce dimerization of RNase L using DNA-encoded library (DEL) screening.
• To design and validate a next-generation RiboTAC targeting microRNA-21 (miR-21) for potential triple-negative breast cancer (TNBC) therapy.

Main Methods:

• Screening of a DNA-encoded library (DEL) to identify RNase L monomers binders.
• Design of a RiboTAC incorporating a Dovitinib-based RNA-binding module targeting miR-21 precursor.
• Evaluation of RiboTAC efficacy in alleviating miR-21-associated cellular phenotype in TNBC cells.

Main Results:

• Identification of a compound that induces RNase L dimerization and activates its ribonuclease activity.
• Successful development of a RiboTAC targeting miR-21 precursor using Dovitinib as the RNA-binding module.
• Demonstrated alleviation of a miR-21-associated cellular phenotype in triple-negative breast cancer cells.

Conclusions:

• DNA-encoded library screening is effective for identifying protein binders for heterobifunctional compounds.
• Reprogramming existing drugs like Dovitinib into RiboTACs enables targeted RNA modulation.
• This approach offers a promising strategy for developing novel RNA-targeting therapeutics, particularly for cancers like TNBC.