Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2).

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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
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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
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)30N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)170N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)100N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)38N/AN/ADetails