LIN28 protein-RNA interaction as drug target

Small-molecule modulators of RNAs is a key activity of the group. With a multi-disciplinary team of collaborators, we are exploring the target potential of LIN28, an oncogenic RNA-binding protein (RBP) which controls biogenesis of let-7 miRNAs.

We began with characterization of the protein-RNA complex using NMR spectroscopy (external pageNat Struct Mol Biol 2012call_made) and novel in vitro assays (external pageNucleic Acids Res 2013call_made), as well as a miniaturized one for small-molecule screening.

One hit molecule (from 16'000 screened) was successfully validated in embryonic stem cells and cancer tumor spheres (external pageACS Chem Biol 2016call_made).

Currently, we are investigating its use in two disease areas: prostate cancer (external pageCancer Res 2016call_made) and myotonic dystrophies, in collaboration with clinical researchers at the Institute of Oncology Research, Bellinzona and the neurology dept. of LMU (DE), respectively.

Taken together, this project demonstrates a generic approach to assessing RBP-RNA interactions as drug targets for small molecule ligands. Specifically, it will allow us to determine whether the Lin28-RNA interaction is a valid drug target in any of several possible disease indications.