Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, protein kinase D, cancer, cardiac hypertrophy, CRT0066101, 3-IN-PP1, GROWTH IN-VITRO, NF-KAPPA-B, C-MU, TYROSINE PHOSPHORYLATION, CARDIAC-HYPERTROPHY, CATALYTIC-ACTIVITY, MOLECULAR-CLONING, CANCER, ACTIVATION, POTENT, Animals, Dose-Response Relationship, Drug, Drug Development, Humans, Molecular Structure, Protein Kinase C, Protein Kinase Inhibitors, Structure-Activity Relationship, 1SA1121N|1SA1123N#55305954, C24/17/074#54270814, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

Protein kinase D (PKD) is a serine/threonine kinase family belonging to the Ca2+/calmodulin-dependent protein kinase group. Since its discovery two decades ago, many efforts have been put in elucidating PKD's structure, cellular role and functioning. The PKD family consists of three highly homologous isoforms: PKD1, PKD2 and PKD3. Accumulating cell-signaling research has evidenced that dysregulated PKD plays a crucial role in the pathogenesis of cardiac hypertrophy and several cancer types. These findings led to a broad interest in the design of small-molecule protein kinase D inhibitors. In this review, we present an extensive overview on the past and recent advances in the discovery and development of PKD inhibitors. The focus extends from broad-spectrum kinase inhibitors used in PKD signaling experiments to intentionally developed, bioactive PKD inhibitors. Finally, attention is paid to PKD inhibitors that have been identified as an off-target through large kinome screening panels.