Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs

Abstract

Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable.

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

“…Further pre-clinical studies are required to ascertain if DROSHA, DICER, and their variants are therapeutic targets or biomarkers in neuroblastoma. Topoisomerase inhibitors are predicted to inhibit DROSHA and DICER pri-miRNA interactions [143], and additional computer simulations suggest that three metabolites interfere with DICER pri-miRNA-binding [144], but in cellulo validation is required.…”

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

“…Moreover, some small-molecule ligands identified as highly basic and polar molecules tend to bind to RNAs with high affinity but low selectivity (Guan and Disney, 2012;Connelly et al, 2016). Thus far, a number of strategies have been developed and used to design and/or identify small molecules that can bind to RNA targets, such as binding-or phenotype-based screening (Mei et al, 1997;Sztuba-Solinska et al, 2014;Howe et al, 2015;Prado et al, 2016;Rizvi et al, 2018;Velagapudi et al, 2018;Green et al, 2019) and computational modeling and structure-or chemoinformatics-based design or virtual screening (Stelzer et al, 2011;Parkesh et al, 2012;Nguyen et al, 2015;Disney et al, 2016;Luu et al, 2016). These efforts have led to the discovery and development of chemically diverse small molecules targeting RNAs, with many exhibiting more drug-like structural and physicochemical properties (Fig.…”

“…A small-molecule microarray-based approach was also developed for the identification of binders of RNA motifs (Velagapudi et al, 2018). After screening against a library of 727 pharmacologically active compounds being used in the clinic or human trials, a number of DNA-intercalating agents (and topoisomerases inhibitors), such as doxorubicin, ellipticine, and mitoxantrone, as well as other entities, were revealed to bind to RNAs.…”

Unveiling the druggable RNA targets and small molecule therapeutics

“…Absorb Array is a recent advancement in SMM technology developed by the Disney laboratory. 185 Here, small molecule compounds are non-covalently absorbed onto a hydrate agarose-coated microarray surface, creating a chemically unmodified library for binding to radiolabeled RNA motif libraries. This approach is meant to avoid the addition of functional groups for covalent immobilization of the chemotypes to the array, which could influence the molecular recognition of the parent compound's natural targets.…”

“…196 StARTS and HiT-StARTS can be used in tandem with Inforna, a bioinformatics-based approach that integrates RNA motif-small molecule interactions identified via 2DCS and structural data of target RNAs. 185,196,197 Inforna generates lead compounds for an RNA of interest by comparing the motifs found in the RNA target's structure with the RNA motif-small-molecule interactions in its database.…”