| Literature DB >> 18951790 |
Joey L Methot1, Christopher L Hamblett, Dawn M Mampreian, Joon Jung, Andreas Harsch, Alexander A Szewczak, William K Dahlberg, Richard E Middleton, Bethany Hughes, Judith C Fleming, Hongmei Wang, Astrid M Kral, Nicole Ozerova, Jonathan C Cruz, Brian Haines, Melissa Chenard, Candia M Kenific, J Paul Secrist, Thomas A Miller.
Abstract
A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.Entities:
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Year: 2008 PMID： 18951790 DOI： 10.1016/j.bmcl.2008.10.052
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823