Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit

Abstract

A hypoxic state is critical to the metastatic and invasive characteristics of cancer. Numerous pathways play critical roles in cancer maintenance, many of which include noncoding RNAs such as microRNA (miR)-210 that regulates hypoxia inducible factors (HIFs). Herein, we describe the identification of a small molecule named Targapremir-210 that binds to the Dicer site of the miR-210 hairpin precursor. This interaction inhibits production of the mature miRNA, derepresses glycerol-3-phosphate dehydrogenase 1-like enzyme (GPD1L), a hypoxia-associated protein negatively regulated by miR-210, decreases HIF-1α, and triggers apoptosis of triple negative breast cancer cells only under hypoxic conditions. Further, Targapremir-210 inhibits tumorigenesis in a mouse xenograft model of hypoxic triple negative breast cancer. Many factors govern molecular recognition of biological targets by small molecules. For protein, chemoproteomics and activity-based protein profiling are invaluable tools to study small molecule target engagement and selectivity in cells. Such approaches are lacking for RNA, leaving a void in the understanding of its druggability. We applied Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP) to study the cellular selectivity and the on- and off-targets of Targapremir-210. Targapremir-210 selectively recognizes the miR-210 precursor and can differentially recognize RNAs in cells that have the same target motif but have different expression levels, revealing this important feature for selectively drugging RNAs for the first time. These studies show that small molecules can be rapidly designed to selectively target RNAs and affect cellular responses to environmental conditions, resulting in favorable benefits against cancer. Further, they help define rules for identifying druggable targets in the transcriptome.

Synthesis and Evaluation of Chloroquine‐Containing DMAEMA Copolymers as Efficient Anti‐miRNA Delivery Vectors with Improved Endosomal Escape and Antimigratory Activity in Cancer Cells

“…The above results confirm that PDC17‐H effectively delivered anti‐miR‐210 to MDA‐MB‐231 cells and downregulated cellular miR‐210 levels. Previous reports showed that downregulation of miR‐210 inhibits proliferation and induces apoptosis in cancer cells . We thus hypothesized that PDC17‐H/anti‐miR‐210 polyplexes will show improved cell killing activity in cancer cells.…”

The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology

“…The results of this study may be applied to future studies to identify new therapeutic targets against tau-associated diseases. 32,[79][80][81][82] 1: Schematic representation of cell-based assays with mini-genes expressing wild type tau or tau with mutations in intron 9 or 10. 30,32 Mini-genes contain exon 10 in frame with a firefly luciferase reporter gene.…”

Post-transcriptionally impairedde novomutations contribute to the genetic etiology of four neuropsychiatric disorders

“…In this study, our method sheds light on evaluation of post-transcriptional impact of genetic mutations especially for synonymous mutations. Additionally, as small molecules can be rapidly designed to selectively target RNAs and affect RNA-RBP interactions 54 , our study provides new insights into RNA-based therapeutic strategies for the treatment of neuropsychiatric disorders.…”