Design of novel histone deacetylase inhibitors.
Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are of synthetic and therapeutic interest and ongoing clinical studies indicate that they show great promise for the treatment of cancer. Moreover, Zolinza (vorinostat) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma [Nat. Rev. Drug Disc. 2007, 6, 21]. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of HDAC inhibitors, we sought to identify novel HDAC inhibitor structures through iterative design by utilizing low affinity ligands as synthetic starting points for SAR development. Novel and potent HDAC inhibitors have been identified using this approach and herein we report the optimization of the recognition elements of a novel series of malonyl-derived HDAC inhibitors.
Siliphaivanh
Phieng
P
Department of Drug Design & Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Phieng_silphaivanh@merck.com
Harrington
Paul
P
Witter
David J
DJ
Otte
Karin
K
Tempest
Paul
P
Kattar
Sam
S
Kral
Astrid M
AM
Fleming
Judith C
JC
Deshmukh
Sujal V
SV
Harsch
Andreas
A
Secrist
Paul J
PJ
Miller
Thomas A
TA
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors