RNA Aptamer‐Enabled Development of Heterobifunctionals That Chemically Induce RNA‐FKBP12 Ternary Complexes

Limitations in the druggability of challenging protein targets, coupled with recognition of the diverse roles of noncoding RNAs in cellular regulation and disease have spurred interest in RNA as a druggable macromolecule. The rapidly emerging field of RNA‐targeted small‐molecule therapeutics is now exploring induced proximity mechanisms in the form of RNA‐targeting chimeras that recruit effector proteins to catalyze RNA decay. Inspired by “molecular glue” natural products such as rapamycin and cyclosporin A, which induce protein–protein interactions to sterically modulate protein function, we propose the new application of immunophilin recruitment to alter RNA function. Here in, we report the design and characterization of heterobifunctional molecules that induce highly cooperative RNA‐FKBP12 ternary complexes and describe efforts to assess their impact on RNA metabolism. We also evaluate applications and report off‐target liabilities associated with the chosen RNA ligand for our heterobifunctional series. Finally, we discuss the challenges faced and highlight opportunities for future success in the RNA space.