Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif.
Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency and selectivity despite the absence of a surface-binding motif. The binding of these highly efficient ligands for HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high selectivity and potent inhibition of HDAC6 can be achieved through careful choice of linker element only.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Florence F
FF
Wagner
David E
DE
Olson
Jennifer P
JP
Gale
Taner
T
Kaya
Michel
M
Weïwer
Nadia
N
Aidoud
Méryl
M
Thomas
Emeline L
EL
Davoine
Bérénice C
BC
Lemercier
Yan-Ling
YL
Zhang
Edward B
EB
Holson
D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D018716:Molecular Mimicry; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases