Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors

KrennHrubec, Keris; Marshall, Brett; Hedglin, Mark; Verdin, Eric; Ulrich, Scott M.

doi:10.1016/j.bmcl.2007.02.064

Cited by 186 publications

(161 citation statements)

References 21 publications

Supporting

Mentioning

157

Contrasting

Unclassified

Order By: Relevance

“…HDAC8 (24), showing that despite limited structural information, progress is being made in the design of isoform-selective HDACis (28). Further selectivity among the HDACs is possible, with, for example, MS-275, which belongs to the benzamide family of HDACis, selectively inhibiting HDAC1, HDAC2, and HDAC3 but not HDAC6 or HDAC8 (11,29).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple HDAC enzymes have been identified, of which HDAC1 to HDAC10 are expressed in malignant cells (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). To understand the spectrum of HDACs inhibited by droxinostat and determine whether selective HDAC inhibition is sufficient to sensitize cells to FAS and TRAIL, we examined the spectrum of HDAC enzymes inhibited by droxinostat.…”

Section: Droxinostat Selectively Inhibits Hdac3 Hdac6 and Hdac8mentioning

confidence: 99%

See 1 more Smart Citation

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246-56. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Droxinostat Selectively Inhibits Hdac3 Hdac6 and Hdac8mentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…C5 and c6 are investigational compounds (described in [41]) and are available on request. Inhibitors were dissolved in DMSO as a stock of 10 mM.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

Lehmann

Hoffmann

Koch

et al. 2014

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background: Previous studies have shown that class-I histone deacetylase (HDAC) 8 mRNA is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. Using urothelial cancer cell lines we evaluated whether specific targeting of HDAC8 might be a therapeutic option in bladder cancer treatment. Methods: We conducted siRNA-mediated knockdown and specific pharmacological inhibition of HDAC8 with the three different inhibitors compound 2, compound 5, and compound 6 in several urothelial carcinoma cell lines with distinct HDAC8 expression profiles. Levels of HDAC and marker proteins were determined by western blot analysis and mRNA levels were measured by quantitative real-time PCR. Cellular effects of HDAC8 suppression were analyzed by ATP assay, flow cytometry, colony forming assay and migration assay. Results: Efficient siRNA-mediated knockdown of HDAC8 reduced proliferation up to 45%. The HDAC8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (IC 50 9 -21 μM). Flow cytometry revealed only a slight increase in the sub-G1 fraction indicating a limited induction of apoptosis. Expression of thymidylate synthase was partly reduced; PARP-cleavage was not detected. The influence of the pharmacological inhibition on clonogenic growth and migration show a cell line-and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. Conclusions: Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. Accordingly, HDAC8 on its own is not a promising drug target in bladder cancer.

show abstract

“…A specific inhibitor of the class II isoform HDAC6 has been developed, 11,12 and similar attempts have also been made to develop class I isoform-specific inhibitors, particularly HDAC8. 13,14 However, several factors, including the similarity between their catalytic sites, the difficulty in obtaining purified active proteins and until recently, lack of X-ray crystal structures, have hampered the search for potent isoform-specific inhibitors, and this in turn has slowed down the progress in delineating the biology of the individual HDAC isoforms in cancer. 15,16 Knockdown experiments of selective HDAC isoforms have revealed that HDAC8 is essential for cell survival.…”

Section: Introductionmentioning

confidence: 99%

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

et al. 2008

View full text Add to dashboard Cite

We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with 4200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-c1 (PLCc1)-defective line was resistant. Jurkat cells showed a dosedependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca 2 þ flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca 2 þ chelators (BAPTA) and enhanced by Ca 2 þ effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCc1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies.

show abstract

Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors

Cited by 186 publications

References 21 publications

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

Contact Info

Product

Resources

About