Author/Authors :
Joey L. Methot، نويسنده , , Christopher L. Hamblett، نويسنده , , Dawn M. Mampreian، نويسنده , , Yung Joon Jung، نويسنده , , Andreas Harsch، نويسنده , , Alexander A. Szewczak، نويسنده , , William K. Dahlberg، نويسنده , , Richard E. Middleton، نويسنده , , Bethany Hughes، نويسنده , , Judith C. Fleming، نويسنده , , Hongmei Wang، نويسنده , , Astrid M. Kral، نويسنده , , Nicole Ozerova، نويسنده , , Jonathan C. Cruz، نويسنده , , Brian Haines، نويسنده , , Melissa Chenard، نويسنده , , Candia M. Kenific، نويسنده , , J. Paul Secrist، نويسنده , , Thomas A. Miller، نويسنده ,
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.
Keywords :
HDAC inhibitor , Isoform selectivity , HDAC3 , Internal cavity , Spirocycle , biaryl
