Design and synthesis of benzoazepin-2-one analogs as allosteric binders targeting the PIF pocket of PDK1

Bioorganic & Medicinal Chemistry Letters
Linyi WeiYi Liu

Abstract

A novel series of benzoazepin-2-ones were designed and synthesized targeting the PIF pocket of AGC protein kinases, among which a series of thioether-linked benzoazepin-2-ones were discovered to bind to the PIF pocket of 3-phosphoinositide-dependent kinase-1 (PDK1), and to displace the PIF peptide with an EC(50) values in the lower micromolar range. The structure-activity relationships (SARs) of the linker region, tail region, and distal region were explored to further optimize these novel binders which target the PIF pocket of PDK1. When tested in an in vitro PDK1 enzymatic assay using a peptide substrate, the benzodiazepin-2-ones increased the activity of the enzyme in a concentration-dependent fashion, indicating these compounds act as PDK1 allosteric activators. These new compounds may be further developed as therapeutic agents for the treatment of diseases where the PDK1-mediated AGC protein kinases are dysregulated.

Citations

Aug 26, 2011·Journal of Medicinal Chemistry·Wolfgang FröhnerMatthias Engel
Jan 6, 2012·The Journal of Biological Chemistry·Justin HallXiayang Qiu
May 10, 2011·Annual Review of Biochemistry·Arvin C Dar, Kevan M Shokat
Mar 22, 2014·Future Medicinal Chemistry·Sandra W Cowan-JacobStefan Knapp
Dec 19, 2014·Proceedings of the National Academy of Sciences of the United States of America·T Justin RettenmaierJames A Wells
Oct 8, 2015·Journal of Medicinal Chemistry·T Justin RettenmaierJames A Wells
Jun 10, 2016·Nature·Vanessa S Rodrik-OutmezguineKevan M Shokat
Jan 4, 2017·ACS Chemical Biology·Jose M ArencibiaRicardo M Biondi
Feb 9, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Xinyuan XuShaoyong Lu

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