@article{328ef37cc72f429791bb1aa05992b1f7,
title = "Structural Features of Small Molecules Targeting the RNA Repeat Expansion That Causes Genetically Defined ALS/FTD",
abstract = "Genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively named c9ALS/FTD, are triggered by hexanucleotide GGGGCC repeat expansions [r(G4C2)exp] within the C9orf72 gene. In these diseases, neuronal loss occurs through an interplay of deleterious phenotypes, including r(G4C2)exp RNA gain-of-function mechanisms. Herein, we identified a benzimidazole derivative, CB096, that specifically binds to a repeating 1 × 1 GG internal loop structure, 5′CGG/3′GGC, that is formed when r(G4C2)exp folds. Structure-activity relationship (SAR) studies and molecular dynamics (MD) simulations were used to define the molecular interactions formed between CB096 and r(G4C2)exp that results in the rescue of disease-associated pathways. Overall, this study reveals a unique structural feature within r(G4C2)exp that can be exploited for the development of lead medicines and chemical probes.",
author = "Andrei Ursu and Wang, {Kye Won} and Bush, {Jessica A.} and Shruti Choudhary and Chen, {Jonathan L.} and Baisden, {Jared T.} and Zhang, {Yong Jie} and Gendron, {Tania F.} and Leonard Petrucelli and Ilyas Yildirim and Disney, {Matthew D.}",
note = "Funding Information: This work was funded by the NIH (DP1 NS096898 and R35 NS116846 to M.D.D.; P01 NS099114 to M.D.D. and L.P.; and R35 NS097273 to L.P.), Target ALS (to M.D.D.), and the Nelson Family Fund (to M.D.D). A.U. acknowledges the Deutsche Forschungsgemeinschaft (DFG) for the DFG Postdoctoral Fellowship and the ALS Association (ALSA) for the Milton Safenowitz Postdoctoral Fellowship. We thank T. Bailey for the preliminary TO1 high throughput screening efforts. We acknowledge C. Williams, S. Meyer, H. Haniff, Y. Li, H. Aikawa, and the members of the Disney lab for the helpful discussions and valuable input throughout the study. We thank J. Childs-Disney for assistance with writing and editing the manuscript and X. Kong for his assistance in acquiring NMR spectra. Purchase of the 600 MHz NMR instrument was supported in part by the NIH (S10OD021550). Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",
year = "2020",
month = dec,
day = "18",
doi = "10.1021/acschembio.0c00049",
language = "English (US)",
volume = "15",
pages = "3112--3123",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "12",
}