title: Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle.
abstract: PKD-mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Gö-6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Gö-6976 triggered calcium signaling and activated stress-inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Gö-6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD.
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States.
authors: Douglas D
authors: DD
authors: Lemon
authors: Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, United States.
authors: Brooke C
authors: BC
authors: Harrison
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States.
authors: Todd R
authors: TR
authors: Horn
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States.
authors: Matthew S
authors: MS
authors: Stratton
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States.
authors: Bradley S
authors: BS
authors: Ferguson
authors: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States.
authors: Michael F
authors: MF
authors: Wempe
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States. Electronic address: timothy.mckinsey@ucdenver.edu.
authors: Timothy A
authors: TA
authors: McKinsey
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002227:Carbazoles; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C577554:MC1568; D009124:Muscle Proteins; D011758:Pyrroles; C081021:Go 6976; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases
keywords: Class IIa histone deacetylase; Muscle; Protein kinase D; Small molecule inhibitors