MC1568,ClassIIaHDACInhibitor

Biological Activity:

MC1568 is a potent and selective inhibitor of class IIa histone deacetylases (HDACs), with IC₅₀ of 100 nM for maize HD1-A. It is 34-fold more selective for HD1-A than HD1-B, 176-fold more selective for class I HDACs. It exhibits tissue-selective inhibition between members of class II deacetylases in vivo; inhibits HDAC4 and HDAC5 in skeletal muscle and the heart without affecting HDAC3 activity. It arrests myogenesis through the stabilization of myocyte enhancer factor 2D (MEF2D)-HDAC3/4 complex. In a recent study of pancreatic explants, MC1568 enhances expression of Pax4, a key factor required for proper β-and δ-cell differentiation and amplifies endocrine β- and δ-cells.

How to Use:

In vitro:  MC1568 was used at 5-10µM final concentration in vitro and cellular assays.

In vivo: MC1568 could be orally dosed to mice at 50 mg/kg once per day (formulation: 0.5% CMC, 5 mg/mL). It has an apparent tissue-selective HDAC inhibition. In skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 without affecting HDAC3 activity, thereby leaving MEF2-HDAC complexes in a repressed state.

Reference: 

• 1.    Mai A, et al. Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. (2005) J Med Chem. 48(9):3344-53.
• 2.      Mai A, et al. Identification of two new synthetic histone deacetylase inhibitors that modulate globin gene expression in erythroid cells from healthy donors and patients with thalassemia. (2007) Mol Pharmacol.72(5):1111-23.
• 3.      Duong V, et al. Specific activity of class II histone deacetylases in human breast cancer cells.(2008) Mol Cancer Res.6(12):1908-19.
• 4.      Nebbioso A, et al. Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes. (2009) EMBO Rep. 10(7):776-82.
• 5.    Lenoir O, et al. Specific control of pancreatic endocrine β- and δ-cell mass by class IIa histone deacetylases HDAC4, HDAC5, and HDAC9. (2011) Diabetes. 60(11):2861-71.

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