Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2).
Article Details
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Witter DJ, Harrington P, Wilson KJ, Chenard M, Fleming JC, Haines B, Kral AM, Secrist JP, Miller TA
Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2).
Bioorg Med Chem Lett. 2008 Jan 15;18(2):726-31. Epub 2007 Nov 19.
- PubMed ID
- 18060775 [ View in PubMed]
- Abstract
A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Vorinostat Histone deacetylase 1 IC 50 (nM) 30 N/A N/A Details Vorinostat Histone deacetylase 2 IC 50 (nM) 170 N/A N/A Details Vorinostat Histone deacetylase 3 IC 50 (nM) 100 N/A N/A Details Vorinostat Histone deacetylase 6 IC 50 (nM) 38 N/A N/A Details