Small molecules targeting repeat r(CGG) sequences

US10011598B2 · kind B2 · utility

Assignee

• THE SCRIPPS RESEARCH INSTITUTE · US

Inventors

• Matthew D. Disney · North Palm Beach, US
• Biao Liu · Beijing, CN
• Jessica L. Childs-Disney · North Palm Beach, US
• Wang-Yong Yang · Seojong-myeon, KR

Key dates

• Filing date: Jan 23, 2017
• Grant date: Jul 3, 2018
• Expiry date: Jan 23, 2037

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D519/00
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The invention provides a series of bioactive small molecules that target expanded r(CGG) repeats, termed r(CGG)exp, that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5′CGG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Specifically, dimeric compounds incorporating two 9-hydroxyellipticine analog structures can even more potently bind the 5′CGG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG) repeats, such as r(CGG)exp. Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp-protein aggregates.