Modulation of oncogenic miRNA biogenesis using functionalized polyamines

Abstract

MicroRNAs are key factors in the regulation of gene expression and their deregulation has been directly linked to various pathologies such as cancer. The use of small molecules to tackle the overexpression of oncogenic miRNAs has proved its efficacy and holds the promise for therapeutic applications. Here we describe the screening of a 640-compound library and the identification of polyamine derivatives interfering with in vitro Dicer-mediated processing of the oncogenic miR-372 precursor (pre-miR-372). The most active inhibitor is a spermine-amidine conjugate that binds to the pre-miR-372 with a KD of 0.15 µM, and inhibits its in vitro processing with a IC50 of 1.06 µM. The inhibition of miR-372 biogenesis was confirmed in gastric cancer cells overexpressing miR-372 and a specific inhibition of proliferation through de-repression of the tumor suppressor LATS2 protein, a miR-372 target, was observed. This compound modifies the expression of a small set of miRNAs and its selective biological activity has been confirmed in patient-derived ex vivo cultures of gastric carcinoma. Polyamine derivatives are promising starting materials for future studies about the inhibition of oncogenic miRNAs and, to the best of our knowledge, this is the first report about the application of functionalized polyamines as miRNAs interfering agents.

Small molecule recognition of disease-relevant RNA structures

“…In addition to neomycin-nucleobase conjugates, Staedel et al 39 screened a 640-member library for inhibition of Dicer-mediated pre-miR-372 processing to identify novel scaffolds with enhanced potency and selectivity. The top hits were all polyamines, the most potent of which, PA-1, inhibited growth of AGS cells, but not MKN74 cells ( Fig.…”

Synthetic small-molecule RNA ligands: future prospects as therapeutic agents

“…7) as promising structures for intracellular inhibition of oncogenic miRNAs. 91 Very efficient compounds inhibiting oncogenic miRNA biogenesis in a specific manner were also reported by Disney and co-workers who developed a lead identification approach called Inforna as a strategy to identify such compounds. 92,93 First, they developed a library vs. library approach where a large set of small-molecule RNA binders immobilized on microarrays are screened against a large number of RNA motifs, such as bulges or internal loops.…”

Target-Directed Approaches for Screening Small Molecules against RNA Targets

“…The bioactivity of this ligand, measured by cell growth inhibition, was further confirmed in gastric cancer cells. 71…”