Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
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.
Methot
Joey L
JL
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joey_methot@merck.com
Chakravarty
Prasun K
PK
Chenard
Melissa
M
Close
Joshua
J
Cruz
Jonathan C
JC
Dahlberg
William K
WK
Fleming
Judith
J
Hamblett
Christopher L
CL
Hamill
Julie E
JE
Harrington
Paul
P
Harsch
Andreas
A
Heidebrecht
Richard
R
Hughes
Bethany
B
Jung
Joon
J
Kenific
Candia M
CM
Kral
Astrid M
AM
Meinke
Peter T
PT
Middleton
Richard E
RE
Ozerova
Nicole
N
Sloman
David L
DL
Stanton
Matthew G
MG
Szewczak
Alexander A
AA
Tyagarajan
Sriram
S
Witter
David J
DJ
Secrist
J Paul
JP
Miller
Thomas A
TA
D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D020033:Protein Isoforms; D012097:Repressor Proteins; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D012097:Repressor Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases