Low-Molecular Weight Small Molecules Can Potently Bind RNA and Affect Oncogenic Pathways in Cells

RNA is challenging to target with
bioactive small molecules, particularly
those of low molecular weight that bind with sufficient affinity and
specificity. In this report, we developed a platform to address this
challenge, affording a novel bioactive interaction. An RNA-focused
small-molecule fragment collection (n = 2500) was
constructed by analyzing features in all publicly reported compounds
that bind RNA, the largest collection of RNA-focused fragments to
date. The RNA-binding landscape for each fragment was studied by using
a library-versus-library selection with an RNA library displaying
a discrete structural element, probing over 12.8 million interactions,
the greatest number of interactions between fragments and biomolecules
probed experimentally. Mining of this dataset across the human transcriptome
defined a drug-like fragment that potently and specifically targeted
the microRNA-372 hairpin precursor, inhibiting its processing into
the mature, functional microRNA and alleviating invasive and proliferative
oncogenic phenotypes in gastric cancer cells. Importantly, this fragment
has favorable properties, including an affinity for the RNA target
of 300 ± 130 nM, a molecular weight of 273 Da, and quantitative
estimate of drug-likeness (QED) score of 0.8. (For comparison, the
mean QED of oral medicines is 0.6 ± 0.2). Thus, these studies
demonstrate that a low-molecular weight, fragment-like compound can
specifically and potently modulate RNA targets.