title: A series of novel, potent, and selective histone deacetylase inhibitors.
abstract: 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.
authors.affiliation: IRBM/Merck Research Laboratories, Via Pontina km 30,600, 00040 Pomezia, Italy. philip_jones@merck.com <philip_jones@merck.com>
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Chakravarty
authors.forename: Ottavia
authors.initials: O
authors.lastname: Cecchetti
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ingenito
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Sergio
authors.initials: S
authors.lastname: Serafini
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
mesh_terms: 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
chemical_list: D000577:Amides; D000596:Amino Acids; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D007527:Isoenzymes; D006655:Histone Deacetylases