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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Methot JL,Hamblett CL,Mampreian DM,Jung J,Harsch A,Szewczak AA,Dahlberg WK,Middleton RE,Hughes B,Fleming JC,Wang H,Kral AM,Ozerova N,Cruz JC,Haines B,Chenard M,Kenific CM,Secrist JP,Miller TAdoi
10.1016/j.bmcl.2008.10.052subject
Has Abstractpub_date
2008-12-01 00:00:00pages
6104-9issue
23eissn
0960-894Xissn
1464-3405pii
S0960-894X(08)01213-4journal_volume
18pub_type
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