- Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
Bioorganic & medicinal chemistry letters (2008-01-10)
Joey L Methot, Prasun K Chakravarty, Melissa Chenard, Joshua Close, Jonathan C Cruz, William K Dahlberg, Judith Fleming, Christopher L Hamblett, Julie E Hamill, Paul Harrington, Andreas Harsch, Richard Heidebrecht, Bethany Hughes, Joon Jung, Candia M Kenific, Astrid M Kral, Peter T Meinke, Richard E Middleton, Nicole Ozerova, David L Sloman, Matthew G Stanton, Alexander A Szewczak, Sriram Tyagarajan, David J Witter, J Paul Secrist, Thomas A Miller
PMID18182289
ZUSAMMENFASSUNG
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
MATERIALIEN