The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control the differentiation of diverse cell types including skeletal, cardiac and smooth muscle cells, neurons, chondrocytes, lymphocytes, endothelial cells and neural crest cells. Class II histone deacetylase (HDAC) proteins bind to MEF2 and regulate MEF2 activity in a calcium-dependent manner in response to various signaling cascades. The crystal structure of a HDAC9/MEF2/DNA complex reveals that HDAC9 binds to a hydrophobic groove of the MEF2 dimer.
ChemDiv proposes the new library of MEF2-HDAC (class II) inhibitors/modulators. This library represents a selection of drug-like compounds aimed at modulating protein-protein interaction (PPI) of MEF2 with HDAC 4, 5, 7 or 9 involved in significant physiological processes. The library has been assembled using in house structural biology insight, molecular stimulation-modeling, virtual screening of ChemDiv’s novel chemistries and medicinal chemistry filtering/ranking of the resulting hits. A representative example of a ‘druggable’ ‘hot spots’ included specific topological features of the MEF2-HDAC interaction (e.g. helix- or beta-sheet mimetics).
Medicinal and Computational Chemistry Dept., ChemDiv, Inc.
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