A series of novel, potent, and selective histone deacetylase inhibitors.
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.
Jones
Philip
P
IRBM/Merck Research Laboratories, Via Pontina km 30,600, 00040 Pomezia, Italy. philip_jones@merck.com <philip_jones@merck.com>
Altamura
Sergio
S
Chakravarty
Prasun K
PK
Cecchetti
Ottavia
O
De Francesco
Raffaele
R
Gallinari
Paola
P
Ingenito
Raffaele
R
Meinke
Peter T
PT
Petrocchi
Alessia
A
Rowley
Michael
M
Scarpelli
Rita
R
Serafini
Sergio
S
Steinkühler
Christian
C
D000577:Amides / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D000577:Amides; D000596:Amino Acids; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D007527:Isoenzymes; D006655:Histone Deacetylases