MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by targeting a mRNA for degradation or translational repression. Not surprisingly, aberrant miRNA expression can cause disease, in particular cancers. Herein, we propose a series of investigations to explore the therapeutic potential of compounds that bind a miRNA precursor associated with breast cancer and inhibit its biogenesis in breast cancer cells. These compounds were developed as a direct result of our currently funded R01 grant (R01- GM097455) in which we proposed to develop computational methods to design small molecules that avidly and selectively bind miRNA precursors. These studies have the potential to advance new anti-cancer therapies to the clinic and to enable development of general strategies to target miRNAs that cause other diseases such as Hepatitis C infections, Alzheimer's disease, and heart disease, among others. Our parent R01 grant proposes to: (i) establish a computational approach to identify lead small molecules for a desired RNA target using a database of RNA motif-small molecule interactions and to identify novel RNA targets from transcriptomes;and (ii) use these computational tools to identify lead small molecules that bind human miRNAs and evaluate them for inhibiting biogenesis in mammalian cell lines. Indeed, this approach was employed to rationally design a small molecule that selectively binds an oncogenic miRNA precursor, miR- 96, and inhibits its biogenesis in breast cancer cells. Importantly, miRNA profiling studies reveal that our small molecule is more selective than an antagomir, the state-of-the-art miRNA targeting modality! Thus, this small molecule is an exemplary case to push forward into animal models of cancer and test the hypothesis that small molecules can indeed drug """"""""undruggable"""""""" RNA targets.
The Specific Aims are:
Aim 1 : Evaluate the therapeutic potential of our designed pri-miR-96 small molecule in models of triple negative and metastatic breast cancer.
Aim 2 : Validate in vivo targets, compound selectivity and mechanism of action of our designer compounds. Previously, our group has shown that small molecules can be designed to react with RNA targets in live cells. This covalent approach significantly improves bioactivity (>2500-fold) and can be used to validate the cellular targets of small molecules.
Aim 3 : Evaluate a dimeric small molecule that simultaneously binds the Drosha processing site and an adjacent internal loop in pri-miR-96. We have designed a potent dimeric small molecule that targets pri-miR-96 in vitro (~500-fold more potent than our lead monomeric small molecule). We will evaluate the therapeutic potential of this compound in MDA-MB-231 breast cancer cells and metastatic and drug-resistant variants, using orthotopic xenograft models.

Public Health Relevance

We have designed a small molecule that binds an oncogenic microRNA and inhibits its function in breast cancer cells. We propose to determine the therapeutic potential of this compound and optimize it for bioactivity using two methods established in our laboratory. These studies could result in new cancer therapeutics and a general strategy to target RNAs that cause cancer and other diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Preusch, Peter
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Scripps Florida
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Angelbello, Alicia J; Disney, Matthew D (2018) Bleomycin Can Cleave an Oncogenic Noncoding RNA. Chembiochem 19:43-47
Angelbello, Alicia J; Chen, Jonathan L; Childs-Disney, Jessica L et al. (2018) Using Genome Sequence to Enable the Design of Medicines and Chemical Probes. Chem Rev 118:1599-1663
Costales, Matthew G; Matsumoto, Yasumasa; Velagapudi, Sai Pradeep et al. (2018) Small Molecule Targeted Recruitment of a Nuclease to RNA. J Am Chem Soc 140:6741-6744
Haniff, Hafeez S; Graves, Amanda; Disney, Matthew D (2018) Selective Small Molecule Recognition of RNA Base Pairs. ACS Comb Sci 20:482-491
Velagapudi, Sai Pradeep; Luo, Yiling; Tran, Tuan et al. (2017) Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA. ACS Cent Sci 3:205-216
Costales, Matthew G; Haga, Christopher L; Velagapudi, Sai Pradeep et al. (2017) Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit. J Am Chem Soc 139:3446-3455
Disney, Matthew D; Angelbello, Alicia J (2016) Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence. Acc Chem Res 49:2698-2704
Park, HaJeung; Tran, Tuan; Lee, Jun Hyuck et al. (2016) Controlled dehydration improves the diffraction quality of two RNA crystals. BMC Struct Biol 16:19
Velagapudi, Sai Pradeep; Cameron, Michael D; Haga, Christopher L et al. (2016) Design of a small molecule against an oncogenic noncoding RNA. Proc Natl Acad Sci U S A 113:5898-903
Childs-Disney, Jessica L; Disney, Matthew D (2016) Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells. Annu Rev Pharmacol Toxicol 56:123-40

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