325474-22-4Relevant academic research and scientific papers
Identification of Quinolinols as Activators of TEAD-Dependent Transcription
Pobbati, Ajaybabu V.,Mejuch, Tom,Chakraborty, Sayan,Karatas, Hacer,Bharath, Sakshibeedu R.,Guéret, Stéphanie M.,Goy, Pierre-Alexis,Hahne, Gernot,Pahl, Axel,Sievers, Sonja,Guccione, Ernesto,Song, Haiwei,Waldmann, Herbert,Hong, Wanjin
, p. 2909 - 2921 (2019)
The transcriptional co-regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are the vertebrate downstream effectors of the Hippo signaling pathway that controls various physiological and pathological processes. YAP and TAZ pair with the TEAD (TEA domain) family of transcription factors to initiate transcription. We previously identified a tractable pocket in TEADs, which has been physiologically shown to bind palmitate. Herein, a TEAD-palmitate interaction screen was developed to select small molecules occupying the palmitate-binding pocket (PBP) of TEADs. We show that quinolinols were TEAD-binding compounds that augment YAP/TAZ-TEAD activity, which was verified using TEAD reporter assay, RT-qPCR, and RNA-Seq analyses. Structure-activity relationship investigations uncovered the quinolinol substituents that are necessary for TEAD activation. We reveal a novel mechanism where quinolinols stabilize YAP/TAZ protein levels by occupying the PBP. The enhancement of YAP activity by quinolinols accelerates the in vivo wound closure in a mouse wound-healing model. Although small molecules that occupy the PBP have been shown to inhibit YAP/TAZ-TEAD activity, leveraging PBP to activate TEADs is a novel approach.
METHODS OF TREATING CREATINE TRANSPORTER DEFICIENCY
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Paragraph 0611-0612, (2021/10/02)
Disclosed are methods of treating creatine transporter deficiency, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that increases transport of a substrate by a mutant or wild-type creatine transporter. Also disclosed are methods of increasing transport of guanidinoacetic acid or a salt thereof across the blood-brain barrier of a mammal, and methods of decreasing accumulation or the concentration of guanidinoacetic acid or a salt thereof in a mammalian cell.
SMALL MOLECULES TARGETING MUTANT MAMMALIAN PROTEINS
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Paragraph 0235; 0236; 0255, (2021/10/02)
Disclosed are compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with a mutation in a protein.
