Details
Stereochemistry | ACHIRAL |
Molecular Formula | C22H25N3O3 |
Molecular Weight | 379.4522 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 1 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OCCN(CCC1=CNC2=CC=CC=C12)CC3=CC=C(\C=C\C(=O)NO)C=C3
InChI
InChIKey=BWDQBBCUWLSASG-MDZDMXLPSA-N
InChI=1S/C22H25N3O3/c26-14-13-25(12-11-19-15-23-21-4-2-1-3-20(19)21)16-18-7-5-17(6-8-18)9-10-22(27)24-28/h1-10,15,23,26,28H,11-14,16H2,(H,24,27)/b10-9+
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/18927309Curator's Comment: description was created based on several sources, including
http://www.ncbi.nlm.nih.gov/pubmed/15171259 | https://www.ncbi.nlm.nih.gov/pubmed/14529481 | https://www.ncbi.nlm.nih.gov/pubmed/15496978 | https://www.ncbi.nlm.nih.gov/pubmed/21073160
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18927309
Curator's Comment: description was created based on several sources, including
http://www.ncbi.nlm.nih.gov/pubmed/15171259 | https://www.ncbi.nlm.nih.gov/pubmed/14529481 | https://www.ncbi.nlm.nih.gov/pubmed/15496978 | https://www.ncbi.nlm.nih.gov/pubmed/21073160
Dacinostat (also known as LAQ824), is a hydroxamate histone deacetylase inhibitor with potential anticancer activity. Dacinostat inhibits histone deacetylase enzymatic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays. Tumor cells treated with Dacinostat caused acetylation of HSP90 and degradation of its cargo oncoproteins. Flow cytometry studies revealed that both tumor cell lines and normal diploid fibroblasts arrested in the G2/M phase of the cell cycle after Dacinostat treatment. However, an increased sub-G1 population at 48 h (reminiscent of apoptotic cells) was only observed in the cancer cell lines treated with Dacinostat. Dacinostat exhibited antitumor effects in a xenograft animal models. In phase I trials, Dacinostat was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition. In another phase 1 in patients with advanced solid tumors, grade 3 or 4 toxicities were observed. Dacinostat had been in phase II clinical trials by Novartis for the treatment of solid tumors but further studies were discontinued.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2093865 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14521422 |
32.0 nM [IC50] | ||
Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18308563 |
2.6 nM [IC50] | ||
Target ID: CHEMBL1937 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17941625 |
7.0 nM [IC50] | ||
Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18308563 |
3.6 nM [IC50] | ||
Target ID: CHEMBL3524 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17956988 |
1.0 nM [IC50] | ||
Target ID: CHEMBL2563 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
5.6 nM [IC50] | ||
Target ID: CHEMBL1865 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
5.9 nM [IC50] | ||
Target ID: CHEMBL2716 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
6.1 nM [IC50] | ||
Target ID: CHEMBL3192 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
3.8 nM [IC50] | ||
Target ID: CHEMBL4145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
8.2 nM [IC50] | ||
Target ID: CHEMBL5103 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
8.4 nM [IC50] | ||
Target ID: CHEMBL3310 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160 |
5.6 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
moderate | ||||
weak | ||||
weak | ||||
weak | ||||
weak | ||||
weak | ||||
yes [IC50 14 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. | 2005 Nov |
|
Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. | 2007 Jan |
|
Chemical phylogenetics of histone deacetylases. | 2010 Mar |
|
Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. | 2011 Jul 14 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18927309
LAQ824 (Dacinostat) was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. The starting dose of 6 mg/m^2/d. Minimal toxicity was
observed at the first five dose levels (6-48 mg/m^2/d); no dose-limiting toxicity was reported at the 6 and 12 mg/m^2/d dose levels.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21073160
HCT-116 and NCI-H460 tumor cell lines were grown in a volume of 200 μL at approximately 10% confluency in 96-well multitier plates and were allowed to recover for an additional 24 h. Tumor cells were treated with either varying concentrations of Dacinostat or solvent for 24 h. After the cells had been treated, the plates were washed to remove drug and incubated for 48 h. The fraction of cells surviving after compound treatment was determined using the SRB assay.
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NCI_THESAURUS |
C1946
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8388
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ACTIVE MOIETY