title: Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.
abstract: Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.
authors.affiliation: Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139, United States. michael.shultz@novartis.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.forename: Xueying
authors.initials: X
authors.lastname: Cao
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chen
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Cho
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Davis
authors.forename: Joe
authors.initials: J
authors.lastname: Eckman
authors.forename: Jianmei
authors.initials: J
authors.lastname: Fan
authors.forename: Alex
authors.initials: A
authors.lastname: Fekete
authors.forename: Brant
authors.initials: B
authors.lastname: Firestone
authors.forename: Julie
authors.initials: J
authors.lastname: Flynn
authors.forename: Jack
authors.initials: J
authors.lastname: Green
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Growney
authors.forename: Mats
authors.initials: M
authors.lastname: Holmqvist
authors.forename: Meier
authors.initials: M
authors.lastname: Hsu
authors.forename: Daniel
authors.initials: D
authors.lastname: Jansson
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Paul
authors.initials: P
authors.lastname: Kwon
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Franco
authors.initials: F
authors.lastname: Lombardo
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Dyuti
authors.initials: D
authors.lastname: Majumdar
authors.forename: Christopher
authors.initials: C
authors.lastname: Meta
authors.forename: Lawrence
authors.initials: L
authors.lastname: Perez
authors.forename: Minying
authors.initials: M
authors.lastname: Pu
authors.forename: Tim
authors.initials: T
authors.lastname: Ramsey
authors.forename: Stacy
authors.initials: S
authors.lastname: Remiszewski
authors.forename: Suzanne
authors.initials: S
authors.lastname: Skolnik
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.forename: Laszlo
authors.initials: L
authors.lastname: Urban
authors.forename: Vinita
authors.initials: V
authors.lastname: Uttamsingh
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Steven
authors.initials: S
authors.lastname: Whitebread
authors.forename: Lewis
authors.initials: L
authors.lastname: Whitehead
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan-Neale
authors.forename: Yung-Mae
authors.initials: YM
authors.lastname: Yao
authors.forename: Liping
authors.initials: L
authors.lastname: Zhou
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D045325:HCT116 Cells; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000606913:KCNH2 protein, human; C561235:N-hydroxy-3-(4-(((2-(2-(1-hydroxy-1-methylethyl)-1H-indol-3-yl)ethyl)isopropylamino)methyl)phenyl)acrylamide; C561236:N-hydroxy-3-(4-((2-(2-methylpyrazolo(1,5-a)pyridin-3-yl)ethylamino)methyl)phenyl)acrylamide