title: Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D.
abstract: Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency. We describe herein the synthesis and biological evaluation of novel benzothienothiazepinone analogs. We achieved a ten-fold increase in the in vitro PKD1 inhibitory potency for the second generation lead kb-NB142-70 and accomplished a transition to an almost equally potent novel pyrimidine scaffold, while maintaining excellent target selectivity. These promising results will guide the design of pharmacological tools to dissect PKD function and pave the way for the development of potential anti-cancer agents.
authors: Department of Chemistry, University of Pittsburgh, Pittsburgh PA 15260, United States of America.
authors: Karla
authors: K
authors: Bravo-Altamirano
authors: Kara M
authors: KM
authors: George
authors: Marie-Céline
authors: MC
authors: Frantz
authors: Courtney R
authors: CR
authors: Lavalle
authors: Manuj
authors: M
authors: Tandon
authors: Stephanie
authors: S
authors: Leimgruber
authors: Elizabeth R
authors: ER
authors: Sharlow
authors: John S
authors: JS
authors: Lazo
authors: Q Jane
authors: QJ
authors: Wang
authors: Peter
authors: P
authors: Wipf
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