Q. Jane Wang

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 Biomedical Science Tower, Pittsburgh, PA 15261, USA

Abstract:

Protein Kinase D (PKD) comprises a family of serine/threonine kinases that play an important role in regulating a variety of cellular processes. Dysregulation of PKD has been linked to multiple diseases including cancer and cardiovascular disorders. PKD actively contributes to pathological processes such as tumor growth, metastasis, angiogenesis, inflammation, and cardiac hypertrophy, making PKD an attractive therapeutic target for drug development. The lack of a PKD-specific inhibitor has hindered the analysis and targeting of PKD in biological processes. Here, we describe several studies that aim at identifying and developing potent and selective PKD small molecule inhibitors for therapeutic application. Using an in vitro activity-based high throughput screening assay, we have identified first-in-class potent, cell active and kinase-selective inhibitors for the PKD family. A series of analogs are prepared for an atypical PKD inhibitor CID755673 and their in vitro inhibitory potency and cellular activity have been evaluated. A lead structure kb-NB142-70 with low nanomolar potency is derived and further optimized to improve selectivity and in vivo PK/PD profiles. Additional novel PKD inhibitory chemotypes are identified through analysis of targeted small molecule libraries. These novel active site-directed PKD inhibitors exhibit remarkable structural diversity, high potency and selectivity, representing promising leads for further development into selective and therapeutically effective small molecule PKD inhibitors.