Abexinostat
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MedKoo CAT#: 202170

CAS#: 783355-60-2 (free base)

Description: Abexinostat, also known as PCI-24781 or CRA-024781, is novel, broad-spectrum hydroxamic acid-based inhibitor of histone deacetylase (HDAC) with potential antineoplastic activity. Abexinostat inhibits several isoforms of HDAC, resulting in an accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; and the tumor suppressor protein-mediated inhibition of tumor cell division and induction of tumor cell apoptosis.


Chemical Structure

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Abexinostat
CAS# 783355-60-2 (free base)

Theoretical Analysis

MedKoo Cat#: 202170
Name: Abexinostat
CAS#: 783355-60-2 (free base)
Chemical Formula: C21H23N3O5
Exact Mass: 397.16377
Molecular Weight: 397.42
Elemental Analysis: C, 63.46; H, 5.83; N, 10.57; O, 20.13

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25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 850.0 Same day
500.0mg USD 1550.0 Same day
1.0g USD 2750.0 Same day
2.0g USD 4650.0 Same day
5.0g USD 7450.0 Same day
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Related CAS #: 783356-67-2 (HCl)   783355-60-2 (free base)  

Synonym: CRA-024781; CRA 024781; CRA024781; PCI24781; PCI-24781; PCI 24781; Abexinostat.

IUPAC/Chemical Name: 3-(dimethylaminomethyl)-N-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide

InChi Key: MAUCONCHVWBMHK-UHFFFAOYSA-N

InChi Code: InChI=1S/C21H23N3O5/c1-24(2)13-17-16-5-3-4-6-18(16)29-19(17)21(26)22-11-12-28-15-9-7-14(8-10-15)20(25)23-27/h3-10,27H,11-13H2,1-2H3,(H,22,26)(H,23,25)

SMILES Code: O=C(C(O1)=C(CN(C)C)C2=C1C=CC=C2)NCCOC3=CC=C(C(NO)=O)C=C3

Appearance: white to off-white solid powder

Purity: >96% (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 Customs.

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 in water

Shelf Life: >2 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

Biological target: Abexinostat (CRA 024781) is a pan-HDAC inhibitor mostly targeting HDAC1 with Ki of 7 nM.
In vitro activity: Abexinostat enhanced both osteoblast and adipocyte differentiation, and thus it is plausible that it targets the initial phase of commitment of hMSCs to both adipocytic and osteoblastic lineages. The previously mentioned and discussed data from DNA microarrays and ChIP-seq corroborate this hypothesis because they clearly demonstrate the induction of multiple gene and genetic pathways associated with hMSC lineage commitment. This hypothesis and its potential molecular mechanism are illustrated in the current working model (Fig. 6). Interestingly, despite marked global increase in H3K9Ac, this study observed overall fewer enriched genes in the abexinostat-treated cells compared with the control (Fig. 4D). Therefore, it seems as if abexinostat is targeting specific genomic regions, which normally have low H3K9Ac, including those related to hMSC differentiation. On the other hand, genes with high basal H3K9ac signal are not benefiting much from abexinostat. Thus, acetylation marks appear to be being diverged from genes with high basal H3K9Ac signal (such as GAPDH) to those with low basal H3K9Ac signal (such as CEBPA, PPARγ, SP7, and ALPL). Nonetheless, a plausible role for abexinostat in targeting non-H3K9 residues for acetylation or the increase in hMSC commitment could also contribute to the observed phenotype. Reference: Stem Cells Transl Med. 2016 Aug; 5(8): 1036–1047. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954455/
In vivo activity: An in vivo therapeutic study in BK5.erbB2 mice showed that GBCas sensitive to PCI-24781 treatment (diagnosed as PR (Partial Response)) had greatly reduced levels of p-erbB2 and total erbB2 compared to GBCas refractory to treatment (diagnosed as PG (Progressive Disease)). These results indicate that the inhibitory effect of PCI-24781 was not potent enough to reduce the levels of p-erbB2 and total erbB2 in the PG cases. This hypothesis is supported by results showing that the level of erbB2 mRNA was significantly decreased in gallbladders diagnosed as PR, but not in those diagnosed as PG (Fig. 2). Reference: J Hepatol. 2012 Jul; 57(1): 84–91. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378818/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 16.67 41.95
DMF 50.0 125.81
DMF:PBS (pH 7.2) (1:3) 0.1 0.25
Ethanol 3.0 7.55
5% TFA 3.0 7.55

Preparing Stock Solutions

The following data is based on the product molecular weight 397.42 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. Ali D, Hamam R, Alfayez M, Kassem M, Aldahmash A, Alajez NM. Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells Transl Med. 2016 Aug;5(8):1036-47. doi: 10.5966/sctm.2015-0331. Epub 2016 May 18. PMID: 27194745; PMCID: PMC4954455. 2. Bhalla S, Evens AM, Prachand S, Schumacker PT, Gordon LI. Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma. PLoS One. 2013 Nov 27;8(11):e81333. doi: 10.1371/journal.pone.0081333. PMID: 24312289; PMCID: PMC3842257. 3. Salvador MA, Wicinski J, Cabaud O, Toiron Y, Finetti P, Josselin E, Lelièvre H, Kraus-Berthier L, Depil S, Bertucci F, Collette Y, Birnbaum D, Charafe-Jauffret E, Ginestier C. The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression. Clin Cancer Res. 2013 Dec 1;19(23):6520-31. doi: 10.1158/1078-0432.CCR-13-0877. Epub 2013 Oct 18. PMID: 24141629. 4. Kitamura T, Connolly K, Ruffino L, Ajiki T, Lueckgen A, DiGiovanni J, Kiguchi K. The therapeutic effect of histone deacetylase inhibitor PCI-24781 on gallbladder carcinoma in BK5.erbB2 mice. J Hepatol. 2012 Jul;57(1):84-91. doi: 10.1016/j.jhep.2012.01.018. Epub 2012 Feb 9. PMID: 22326466; PMCID: PMC3378818.
In vitro protocol: 1. Ali D, Hamam R, Alfayez M, Kassem M, Aldahmash A, Alajez NM. Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells Transl Med. 2016 Aug;5(8):1036-47. doi: 10.5966/sctm.2015-0331. Epub 2016 May 18. PMID: 27194745; PMCID: PMC4954455. 2. Bhalla S, Evens AM, Prachand S, Schumacker PT, Gordon LI. Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma. PLoS One. 2013 Nov 27;8(11):e81333. doi: 10.1371/journal.pone.0081333. PMID: 24312289; PMCID: PMC3842257.
In vivo protocol: 1. Salvador MA, Wicinski J, Cabaud O, Toiron Y, Finetti P, Josselin E, Lelièvre H, Kraus-Berthier L, Depil S, Bertucci F, Collette Y, Birnbaum D, Charafe-Jauffret E, Ginestier C. The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression. Clin Cancer Res. 2013 Dec 1;19(23):6520-31. doi: 10.1158/1078-0432.CCR-13-0877. Epub 2013 Oct 18. PMID: 24141629. 2. Kitamura T, Connolly K, Ruffino L, Ajiki T, Lueckgen A, DiGiovanni J, Kiguchi K. The therapeutic effect of histone deacetylase inhibitor PCI-24781 on gallbladder carcinoma in BK5.erbB2 mice. J Hepatol. 2012 Jul;57(1):84-91. doi: 10.1016/j.jhep.2012.01.018. Epub 2012 Feb 9. PMID: 22326466; PMCID: PMC3378818.

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1: Correction: Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma. Clin Cancer Res. 2015 Apr 1;21(7):1774-5. doi: 10.1158/1078-0432.CCR-15-0351. PubMed PMID: 25833311.

2: Sholler GS, Currier EA, Dutta A, Slavik MA, Illenye SA, Mendonca MC, Dragon J, Roberts SS, Bond JP. PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma. J Cancer Ther Res. 2013 Dec 28;2:21. PubMed PMID: 25520806; PubMed Central PMCID: PMC4266584.

3: Zhang W, Lv S, Liu J, Zang Z, Yin J, An N, Yang H, Song Y. PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway. Genet Mol Biol. 2014 Oct;37(4):716-24. doi: 10.1590/S1415-47572014005000011. Epub 2014 Oct 21. PubMed PMID: 25505847; PubMed Central PMCID: PMC4261972.

4: He WL, Li YH, Hou WJ, Ke ZF, Chen XL, Lu LY, Cai SR, Song W, Zhang CH, He YL. RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer. World J Gastroenterol. 2014 Aug 7;20(29):10094-107. doi: 10.3748/wjg.v20.i29.10094. PubMed PMID: 25110436; PubMed Central PMCID: PMC4123338.

5: Zhan Q, Tsai S, Lu Y, Wang C, Kwan Y, Ngai S. RuvBL2 is involved in histone deacetylase inhibitor PCI-24781-induced cell death in SK-N-DZ neuroblastoma cells. PLoS One. 2013 Aug 16;8(8):e71663. doi: 10.1371/journal.pone.0071663. eCollection 2013. PubMed PMID: 23977108; PubMed Central PMCID: PMC3745445.

6: Fouliard S, Robert R, Jacquet-Bescond A, du Rieu QC, Balasubramanian S, Loury D, Loriot Y, Hollebecque A, Kloos I, Soria JC, Chenel M, Depil S. Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I. Eur J Cancer. 2013 Sep;49(13):2791-7. doi: 10.1016/j.ejca.2013.05.009. Epub 2013 Jun 18. PubMed PMID: 23790467.

7: Chalret du Rieu Q, Fouliard S, Jacquet-Bescond A, Robert R, Kloos I, Depil S, Chatelut E, Chenel M. Application of hematological toxicity modeling in clinical development of abexinostat (S-78454, PCI-24781), a new histone deacetylase inhibitor. Pharm Res. 2013 Oct;30(10):2640-53. doi: 10.1007/s11095-013-1089-1. Epub 2013 Jun 5. PubMed PMID: 23737346.

8: Kitamura T, Connolly K, Ruffino L, Ajiki T, Lueckgen A, DiGiovanni J, Kiguchi K. The therapeutic effect of histone deacetylase inhibitor PCI-24781 on gallbladder carcinoma in BK5.erbB2 mice. J Hepatol. 2012 Jul;57(1):84-91. doi: 10.1016/j.jhep.2012.01.018. Epub 2012 Feb 9. PubMed PMID: 22326466; PubMed Central PMCID: PMC3378818.

9: Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z. Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines. Anticancer Res. 2011 Apr;31(4):1115-23. PubMed PMID: 21508354; PubMed Central PMCID: PMC3744220.

10: Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z. Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells. Cancer Chemother Pharmacol. 2011 Feb;67(2):439-46. doi: 10.1007/s00280-010-1344-7. Epub 2010 May 12. PubMed PMID: 20461381.



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