Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs

Disney, Matthew D.; Winkelsas, Audrey M.; Velagapudi, Sai Pradeep; Southern, Mark R.; Fallahi, Mohammad; Childs‐Disney, Jessica L.

doi:10.1021/acschembio.6b00001

Cited by 188 publications

(227 citation statements)

References 82 publications

(181 reference statements)

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“…The development of selective compounds that target RNA is difficult, owing to RNA’s anionic nature and the relatively low abundance of most cellular RNAs 10 , among other factors. To identify small molecule leads, we utilized a strategy called Inforna, which identifies highly selective, privileged RNA-motif–small-molecule interactions 11, 12 . Inforna has successfully facilitated the design of potent small-molecule modulators of several RNA repeat expansion disorders 13, 14, 15 and cancer-related microRNAs 11, 16 .…”

Section: Introductionmentioning

confidence: 99%

Precise small-molecule recognition of a toxic CUG RNA repeat expansion

Rzuczek¹,

Colgan²,

Nakai³

et al. 2016

Nat Chem Biol

167

246

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Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context.

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Section: Introductionmentioning

confidence: 99%

Precise small-molecule recognition of a toxic CUG RNA repeat expansion

Rzuczek¹,

Colgan²,

Nakai³

et al. 2016

Nat Chem Biol

167

246

View full text Add to dashboard Cite

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“…(3) The data from 2DCS are compiled into a database that is mined against folded RNA structures within the human transcriptome to identify potentially druggable RNA targets from sequence via an approach named Inforna. (4, 5)…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…At the same time, some of the most successful screens have been conducted on RNA-targeted libraries generated by the diversification of molecular scaffolds known to interact with RNA, such as phenylbenzamidazoles, 38-40 oxazolidinones, 41-44 and diphenylfurans 45-47 though the library sizes and number of scaffolds tested has been fairly limited. 40,48 Based on these results, we see an urgent need for the identification and development of new RNA-targeted scaffolds that can expand scientists' repertoire for probing RNA structure and function, particularly RNA structures critical to infectious agents such as HIV.…”

Section: Introductionmentioning

confidence: 99%

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

et al. 2017

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Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [1H-13C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members. Cheminformatic analysis revealed distinct differences between selective and non-selective ligands. In this study, we evolved dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule:RNA interactions.

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Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs

Cited by 188 publications

References 82 publications

Precise small-molecule recognition of a toxic CUG RNA repeat expansion

Precise small-molecule recognition of a toxic CUG RNA repeat expansion

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

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

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