Dacinostat
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MedKoo CAT#: 200845

CAS#: 404951-53-7 (free base)

Description: Dacinostat, also known as LAQ824, is a hydroxamate histone deacetylase inhibitor with potential anticancer activity. LAQ824 sensitized nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation. LAQ824 reduced clonogenic survival of the H23 and H460 cell lines five-fold compared with controls and four-fold compared with either agent alone (P<0.001). In phase I trials, LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.


Chemical Structure

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Dacinostat
CAS# 404951-53-7 (free base)

Theoretical Analysis

MedKoo Cat#: 200845
Name: Dacinostat
CAS#: 404951-53-7 (free base)
Chemical Formula: C22H25N3O3
Exact Mass: 379.18959
Molecular Weight: 379.45
Elemental Analysis: C, 69.64; H, 6.64; N, 11.07; O, 12.65

Price and Availability

Size Price Availability Quantity
50.0mg USD 250.0 2 Weeks
100.0mg USD 450.0 2 Weeks
200.0mg USD 750.0 2 Weeks
500.0mg USD 1550.0 2 Weeks
1.0g USD 2650.0 2 Weeks
2.0g USD 4250.0 2 Weeks
5.0g USD 5950.0 2 Weeks
10.0g USD 9650.0 2 Weeks
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Related CAS #: 404951-53-7 (free base)   591207-53-3 (free base)   Dacinostat HCl    

Synonym: NVP-LAQ824; NVP-LAQ 824; NVP-LAQ-824; LAQ-824; LAQ824; LAQ 824; Dacinostat.

IUPAC/Chemical Name: (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide

InChi Key: BWDQBBCUWLSASG-MDZDMXLPSA-N

InChi Code: 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+

SMILES Code: O=C(NO)/C=C/C1=CC=C(CN(CCO)CCC2=CNC3=C2C=CC=C3)C=C1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Custom

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: soluble in DMSO, not soluble in water.

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: Dacinostat is a potent HDAC inhibitor, with an IC50 of 32 nM that also inhibits HDAC1 with an IC50 of 9 nM, and is used in cancer research.
In vitro activity: It was determined whether the acquisition of inflammatory properties by LAQ824-treated macrophages renders these cells better activators of antigen-specific CD4+ T-cells. PEMs were therefore treated with LAQ824, LPS or a combination of LPS plus LAQ824 for 24 hours. Following this treatment, naïve CD4+ T-cells specific for a MHC Class II restricted epitope of influenza hemagglutinin (HA) were added to the PEM monolayer and stimulated, or not, with cognate HA-peptide. LAQ824-treated PEMs triggered an enhanced effector function of clonotypic CD4+ T cells, as determined by their capacity to produce higher levels of IFN-γ in response to cognate peptide (Figure 5A-bottom). LAQ824-treated PEMs effectively prime naïve antigen-specific CD4+ T-cells and restore the responsiveness of anergic CD4+ T-cells. As shown in Figure 5D, IL-10 blockade was insufficient to enhance the APC function of LPS-treated macrophages to augment IFN-γ production by CD4+ T-cells (Fig. 5D, LPS alone, black bar versus gray bar), nor was it able to significantly enhance the effect of LAQ824 treatment (Fig. 5D, LAQ+LPS, black bar versus gray bar). Taken together, these data point to a contributory role of IL-10 inhibition in the enhanced APC function displayed by LAQ824-treated macrophages since this effect was reversed when recombinant IL-10 was added-back to the cultures. Reference: J Immunol. 2011 Apr 1;186(7):3986-96. https://pubmed.ncbi.nlm.nih.gov/21368229/
In vivo activity: It was determined whether the in vitro effects correlate with the in vivo activity of NVP-LAQ824 using an immunodeficient mouse model. Immunodeficient BNX mice were inoculated subcutaneously in the flank with 3 × 107 RPMI 8226 MM cells in 100 μL RPMI 1640 medium, together with 100 μL Matrigel. Subcutaneous tumors became palpable in 90% of mice within 3 days and in all mice within 8 days, allowing randomization of mice to either treatment with NVP-LAQ824 or normal saline control cohorts. The data were log-transformed and modeled as a simple linear growth curve. There was no significant difference in the baseline intercept between control and treated groups (P = .83). Daily intraperitoneal administration of NVP-LAQ824 (25 mg/kg) significantly reduced MM tumor growth (Figure 8A-B) and increased survival (Figure 8C), compared with the control group treated with normal saline vehicle only. No significant toxicity, as evidenced by lack of weight changes, was observed in any treatment groups. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM. Reference: Blood. 2003 Oct 1;102(7):2615-22. https://pubmed.ncbi.nlm.nih.gov/12816865/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 56.0 147.58

Preparing Stock Solutions

The following data is based on the product molecular weight 379.45 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther. 2003 Oct;2(10):971-84. PMID: 14578462. 2. Wang H, Cheng F, Woan K, Sahakian E, Merino O, Rock-Klotz J, Vicente-Suarez I, Pinilla-Ibarz J, Wright KL, Seto E, Bhalla K, Villagra A, Sotomayor EM. Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10. J Immunol. 2011 Apr 1;186(7):3986-96. doi: 10.4049/jimmunol.1001101. Epub 2011 Mar 2. PMID: 21368229; PMCID: PMC3998678. 3. . Catley L, Weisberg E, Tai YT, Atadja P, Remiszewski S, Hideshima T, Mitsiades N, Shringarpure R, LeBlanc R, Chauhan D, Munshi NC, Schlossman R, Richardson P, Griffin J, Anderson KC. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood. 2003 Oct 1;102(7):2615-22. doi: 10.1182/blood-2003-01-0233. Epub 2003 Jun 19. PMID: 12816865 4. Leyton J, Alao JP, Da Costa M, Stavropoulou AV, Latigo JR, Perumal M, Pillai R, He Q, Atadja P, Lam EW, Workman P, Vigushin DM, Aboagye EO. In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'[18F]fluorothymidine positron emission tomography. Cancer Res. 2006 Aug 1;66(15):7621-9. doi: 10.1158/0008-5472.CAN-05-3962. PMID: 16885362.
In vitro protocol: 1. Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther. 2003 Oct;2(10):971-84. PMID: 14578462. 2. Wang H, Cheng F, Woan K, Sahakian E, Merino O, Rock-Klotz J, Vicente-Suarez I, Pinilla-Ibarz J, Wright KL, Seto E, Bhalla K, Villagra A, Sotomayor EM. Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10. J Immunol. 2011 Apr 1;186(7):3986-96. doi: 10.4049/jimmunol.1001101. Epub 2011 Mar 2. PMID: 21368229; PMCID: PMC3998678.
In vivo protocol: 1.. Catley L, Weisberg E, Tai YT, Atadja P, Remiszewski S, Hideshima T, Mitsiades N, Shringarpure R, LeBlanc R, Chauhan D, Munshi NC, Schlossman R, Richardson P, Griffin J, Anderson KC. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood. 2003 Oct 1;102(7):2615-22. doi: 10.1182/blood-2003-01-0233. Epub 2003 Jun 19. PMID: 12816865 2. Leyton J, Alao JP, Da Costa M, Stavropoulou AV, Latigo JR, Perumal M, Pillai R, He Q, Atadja P, Lam EW, Workman P, Vigushin DM, Aboagye EO. In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'[18F]fluorothymidine positron emission tomography. Cancer Res. 2006 Aug 1;66(15):7621-9. doi: 10.1158/0008-5472.CAN-05-3962. PMID: 16885362.

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1: Wang H, Cheng F, Woan K, Sahakian E, Merino O, Rock-Klotz J, Vicente-Suarez I, Pinilla-Ibarz J, Wright KL, Seto E, Bhalla K, Villagra A, Sotomayor EM. Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10. J Immunol. 2011 Apr 1;186(7):3986-96. doi: 10.4049/jimmunol.1001101. Epub 2011 Mar 2. PubMed PMID: 21368229.

2: Schwarz K, Romanski A, Puccetti E, Wietbrauk S, Vogel A, Keller M, Scott JW, Serve H, Bug G. The deacetylase inhibitor LAQ824 induces notch signalling in haematopoietic progenitor cells. Leuk Res. 2011 Jan;35(1):119-25. doi: 10.1016/j.leukres.2010.06.024. Epub 2010 Jul 31. PubMed PMID: 20674020.

3: Cho YS, Whitehead L, Li J, Chen CH, Jiang L, Vögtle M, Francotte E, Richert P, Wagner T, Traebert M, Lu Q, Cao X, Dumotier B, Fejzo J, Rajan S, Wang P, Yan-Neale Y, Shao W, Atadja P, Shultz M. Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824). J Med Chem. 2010 Apr 8;53(7):2952-63. doi: 10.1021/jm100007m. PubMed PMID: 20205394.

4: Vo DD, Prins RM, Begley JL, Donahue TR, Morris LF, Bruhn KW, de la Rocha P, Yang MY, Mok S, Garban HJ, Craft N, Economou JS, Marincola FM, Wang E, Ribas A. Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res. 2009 Nov 15;69(22):8693-9. doi: 10.1158/0008-5472.CAN-09-1456. Epub 2009 Oct 27. PubMed PMID: 19861533; PubMed Central PMCID: PMC2779578.

5: Ellis L, Bots M, Lindemann RK, Bolden JE, Newbold A, Cluse LA, Scott CL, Strasser A, Atadja P, Lowe SW, Johnstone RW. The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy. Blood. 2009 Jul 9;114(2):380-93. doi: 10.1182/blood-2008-10-182758. Epub 2009 Apr 21. PubMed PMID: 19383971.

6: de Bono JS, Kristeleit R, Tolcher A, Fong P, Pacey S, Karavasilis V, Mita M, Shaw H, Workman P, Kaye S, Rowinsky EK, Aherne W, Atadja P, Scott JW, Patnaik A. Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin Cancer Res. 2008 Oct 15;14(20):6663-73. doi: 10.1158/1078-0432.CCR-08-0376. PubMed PMID: 18927309.

7: Chung YL, Troy H, Kristeleit R, Aherne W, Jackson LE, Atadja P, Griffiths JR, Judson IR, Workman P, Leach MO, Beloueche-Babari M. Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of a novel histone deacetylase inhibitor, LAQ824, in human colon carcinoma cells and xenografts. Neoplasia. 2008 Apr;10(4):303-13. PubMed PMID: 18392140; PubMed Central PMCID: PMC2288545.

8: Cuneo KC, Fu A, Osusky K, Huamani J, Hallahan DE, Geng L. Histone deacetylase inhibitor NVP-LAQ824 sensitizes human nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation. Anticancer Drugs. 2007 Aug;18(7):793-800. PubMed PMID: 17581301.

9: Kato Y, Salumbides BC, Wang XF, Qian DZ, Williams S, Wei Y, Sanni TB, Atadja P, Pili R. Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. Mol Cancer Ther. 2007 Jan;6(1):70-81. PubMed PMID: 17237267.

10: Leyton J, Alao JP, Da Costa M, Stavropoulou AV, Latigo JR, Perumal M, Pillai R, He Q, Atadja P, Lam EW, Workman P, Vigushin DM, Aboagye EO. In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography. Cancer Res. 2006 Aug 1;66(15):7621-9. PubMed PMID: 16885362.



Additional Information

NVP-LAQ824 inhibits histone deacetylase enzymatic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays. When tested on a variety of solid tumour cell lines, NVP-LAQ824 exhibited selective anti-proliferative effects, inducing cell growth inhibition in some, while inducing cell death in others. To induce cell death, a minimum of 16 h exposure to NVP-LAQ824 is required. Flow cytometry studies revealed that both tumour cell lines and normal diploid fibroblasts arrested in the G2/M phase of the cell cycle after compound treatment. However, an increased sub-G1 population at 48 h (reminiscent of apoptotic cells) was only observed in the cancer cell lines. Annexin V staining data confirmed that NVP-LAQ824 induced apoptosis in tumour cells, but not in normal cells. To relate HDAC inhibition to the anti-proliferative effects of NVP-LAQ824, expression of HDAC 1 was inhibited using antisense and this was sufficient to activate p21 expression, hypophosphorylate Rb and inhibit cell growth. Furthermore, tumour cells treated with NVP-LAQ824 caused acetylation of HSP90 and degradation of its cargo oncoproteins. Finally, NVP-LAQ824 exhibited antitumour effects in a xenograft animal model. To determine if NVP-LAQ824 inhibited histone deacetylases in vivo, tumours treated with the drug were immunoblotted with an antibody specific for acetylated histones H3 and H4 and the results indicated increased histone H3 and 114 acetylation levels in NVP-LAQ824 treated cancer cells. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel HDAC inhibitor is currently in clinical trials as an anticancer agent. see: http://www.ncbi.nlm.nih.gov/pubmed/15171259.