Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors.
In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
Smil
David V
DV
MethylGene Inc, Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1. smild@methylgene.com
Manku
Sukhdev
S
Chantigny
Yves A
YA
Leit
Silvana
S
Wahhab
Amal
A
Yan
Theresa P
TP
Fournel
Marielle
M
Maroun
Christiane
C
Li
Zuomei
Z
Lemieux
Anne-Marie
AM
Nicolescu
Alina
A
Rahil
Jubrail
J
Lefebvre
Sylvain
S
Panetta
Anthony
A
Besterman
Jeffrey M
JM
Déziel
Robert
R
D000107:Acetylation; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D020033:Protein Isoforms; D014404:Tubulin / Q000737:chemistry
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010879:Piperazines; D020033:Protein Isoforms; D014404:Tubulin; D000077489:Piperazine; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases