Biology subjects

Shortridge, M. D.

Publications and source records attributed to Shortridge, M. D..

2 recordsLinked to original sources

bioRxiv2022

Drug-like small molecules that inhibit expression of the oncogenic microRNA-21

We report the discovery of a series of drug-like small molecules which bind specifically to the precursor of the oncogenic and pro-fibrotic microRNA-21 with mid-nanomolar affinity. These molecules are highly ligand-efficient (MW<330) and display specific biochemical and cellular activity by suppressing maturation of miR-21, thereby providing an avenue towards therapeutic intervention in multiple diseases where miR-21 is abnormally expressed. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change, which is not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells.

biochemistry↗

bioRxiv2022

The kinase inhibitor Palbociclib is a potent and specific RNA-binding molecule

The growing awareness of the role of RNA in human disease has motivated significant efforts to discover drug-like small molecules that target RNA. However, high throughput screening campaigns report very low hit rates and generally identify compounds with weak affinity, while most structures reported in Academic studies also lack the pharmacological properties of successful drugs. Even FDA-approved RNA-targeting drugs have only weak (10 M) binding activity. Thus, it is often stated that only complex RNA structures, such as the ribosome or riboswitches, are amenable to small molecule chemistry. We report that the kinase inhibitor Palbociclib/Ibrance is a nM ligand for the HIV-1 TAR. It inhibits recruitment of the positive transcription elongation factor complex at nM concentrations and discriminates >20 fold. We further show that RNA binding can be fully decoupled from kinase inhibition, yielding a new molecule with even higher affinity for RNA. We thus demonstrate that nM affinity, specificity, and potent biochemical activity against undruggable RNAs can be found in the chemical space of blockbuster drugs.

biochemistry↗