Design of a small molecule against an oncogenic noncoding RNA

Velagapudi, Sai Pradeep; Cameron, Michael D.; Haga, Christopher L.; Rosenberg, Laura H.; Lafitte, Marianne; Duckett, Derek R.; Phinney, Donald G.; Disney, Matthew D.

doi:10.1073/pnas.1523975113

Cited by 173 publications

(194 citation statements)

References 38 publications

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“…Recently, small molecules that were designed to target the folded structure of the oncogenic noncoding RNA have shown significant antitumor effects in vivo by selectively modulating noncoding RNAs in cancer cells with no effects in normal cells (45). Additionally, locked nucleic acid (LNA) can serve as a therapeutic agent that specifically targets lncRNAs in vivo (46).…”

Section: Methodsmentioning

confidence: 99%

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

Wang¹,

Zhong²,

Jiang³

et al. 2018

Journal of Clinical Investigation

157

151

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Section: Methodsmentioning

confidence: 99%

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

Wang¹,

Zhong²,

Jiang³

et al. 2018

Journal of Clinical Investigation

157

151

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“…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

166

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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“…The compound also derepressed the effect of miR-96 on FOXO1 expression, enhancing protein amounts by 2-fold when 50 nM of Targaprimir-96 was used. (59) These studies were completed in both MDA-MB-231 (a cellular model of triple negative breast cancer) and 4175 (a breast cancer cell line that metastasizes to lung). (60) Additionally, the compound triggers apoptosis at 50 nM.…”

Section: In Vivo Activity Of Designer Compounds Targeting Oncogenic Nmentioning

confidence: 99%

“…These studies showed that Targaprimir-96 has a favorable pharmacokinetic and metabolism profile as the concentration in serum is greater than 1 μM at 48 h post-IP injection of either 2 or 7 mg/kg, 20-fold higher than the amount of compound needed to trigger apoptosis in cell culture. (59) Thus, the effect of Targaprimir-96 on tumor growth in vivo was assessed. IP injection of 10 mg/kg compound was well tolerated in animals and ablated tumor growth over the course of 21 days.…”

Section: In Vivo Activity Of Designer Compounds Targeting Oncogenic Nmentioning

confidence: 99%

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Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence

Disney

Angelbello

2016

Acc. Chem. Res.

Self Cite

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Conspectus The discovery of RNA catalysis in the 1980s and the dissemination of the human genome sequence at the start of this century inspired investigations of the regulatory roles of noncoding RNAs in biology. In fact, the Encyclopedia of DNA Elements (ENCODE) project has shown that only 1–2% of the human genome encodes protein, yet 75% is transcribed into RNA. Functional studies both preceding and following the ENCODE project have shown that these noncoding RNAs have important roles in regulating gene expression, developmental timing, and other critical functions. RNA’s diverse roles are often a consequence of the various folds that it adopts. The single-stranded nature of the biopolymer enables it to adopt intramolecular folds with noncanonical pairings to lower its free energy. These folds can be scaffolds to bind proteins or to form frameworks to interact with other RNAs. Not surprisingly, dysregulation of certain noncoding RNAs has been shown to be causative of disease. Given this as the background, it is easy to see why it would be useful to develop methods that target RNA and manipulate its biology in rational and predictable ways. The antisense approach has afforded strategies to target RNAs via Watson–Crick base pairing and has typically focused on targeting partially unstructured regions of RNA. Small molecule strategies to target RNA would be desirable not only because compounds could be lead optimized via medicinal chemistry but also because structured regions within an RNA of interest could be targeted to directly interfere with RNA folds that contribute to disease. Additionally, small molecules have historically been the most successful drug candidates. Until recently, the ability to design small molecules that target non-ribosomal RNAs has been elusive, creating the perception that they are “undruggable”. In this Account, approaches to demystify targeting RNA with small molecules are described. Rather than bulk screening for compounds that bind to singular targets, which is the purview of the pharmaceutical industry and academic institutions with high throughput screening facilities, we focus on methods that allow for the rational design of small molecules toward biological RNAs. One enabling and foundational technology that has been developed is two-dimensional combinatorial screening (2DCS), a library-versus-library selection approach that allows the identification of the RNA motif binding preferences of small molecules from millions of combinations. A landscape map of the 2DCS-defined and annotated RNA motif–small molecule interactions is then placed into Inforna, a computational tool that allows one to mine these interactions against an RNA of interest or an entire transcriptome. Indeed, this approach has been enabled by tools to annotate RNA structure from sequence, an invaluable asset to the RNA community and this work, and has allowed for the rational identification of “druggable” RNAs in a target agnostic fashion.

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Design of a small molecule against an oncogenic noncoding RNA

Cited by 173 publications

References 38 publications

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

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

Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence

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