Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle

FEBS Lett. 2015 Apr 28;589(10):1080-8. doi: 10.1016/j.febslet.2015.03.017. Epub 2015 Mar 25.


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.

Keywords: Class IIa histone deacetylase; Muscle; Protein kinase D; Small molecule inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Cell Line
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Mice
  • Muscle Proteins / antagonists & inhibitors*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*


  • Carbazoles
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • MC1568
  • Muscle Proteins
  • Pyrroles
  • Go 6976
  • protein kinase D
  • Protein Kinase C
  • Histone Deacetylases