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MedKoo product information:
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. HDAC, upregulated
in many tumor types, is an an enzyme that is responsible for the
deacetylation of chromatin histone proteins. Check for
active clinical trials or
closed clinical trials using this agent. (NCI
MedKoo Code#: 202170
Exact Mass: 397.16377
Elemental Analysis: C,
63.46; H, 5.83; N, 10.57; O, 20.13
Availability and price:
(CRA-024781) is in stock
10 mg / $150.00
20 mg / $250.00
50 mg / $450.00
100mg / $680.00
200 mg / $980.00
multiple gram available at low
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Quality control data:
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Information about this agent
General information about its properties:
PCI-24781 is a novel, potent, small molecule inhibitor of HDAC enzymes
with anti-tumor activity in vitro and in vivo (Buggy et al Mol Cancer
Ther 2006; 5 (5), p. 1309-1317). Formulation development began with
parenteral administration in the initial Phase I study (PCYC-0401 which
included a single oral dose), and has progressed to an oral capsule
formulation that entered two clinical studies in 2008. The first of
these oral studies (PCYC-0402) is a Phase I, ascending dose study in
patients with solid tumors which has completed enrollment of 39
patients. The second oral study (PCYC-0403) is a Phase I/II trial in
patients with lymphoma in which the Phase I arm has enrolled 25
patients, and the Phase II is due to start in late 2009. In addition, we
anticipate opening a Phase II study in 2009 in sarcoma patients where
the drug is delivered in combination with Adriamycin.
PCI-24781 has an optimized half life, oral
bioavailability, potency, and duration of exposure compared to
competitor drugs (e.g. Zolinza or LBH-589) to achieve an ideal balance
of efficacy with minimal toxicity. The improved potency and
pharmacokinetic aspects of PCI-24781 served as a basis for the ongoing
proof of concept studies in Phase I/II in lymphoma, and subsequently in
additional solid tumor targets as the candidate progresses into its
Phase II program. (source:
PCI-24781 enhances chemotherapy-induced
apoptosis in multidrug-resistant sarcoma cell lines. The
antitumor activity of histone deacetylase inhibitors (HDACI) on
multidrug-resistant sarcoma cell lines has not been previously
described. Treatment of multidrug-resistant sarcoma cell lines with
resulted in dose-dependent accumulation of acetylated histone, p21 and
poly(ADP-ribose)polymerase (PARP) cleavage products. Growth of these
cell lines was inhibited by
IC(50) of 0.43 to 2.7. When we looked for synergy of
chemotherapeutic agents, we found that
reverses drug resistance in all four multidrug-resistant sarcoma cell
lines and synergizes with chemotherapeutic agents to enhance
caspase-3/-7 activity. Expression of RAD51 (a marker for DNA
double-strand break repair) was inhibited and the expression of GADD45α
(a marker for growth arrest and DNA-damage) was induced by
multidrug-resistant sarcoma cell lines. In conclusion, HDACI
synergizes with chemotherapeutic drugs to induce apoptosis and reverses
drug resistance in multidrug-resistant sarcoma cell lines. (source:
1: Singh MM, Manton CA, Bhat KP, Tsai WW, Aldape K,
Barton MC, Chandra J. Inhibition of LSD1 sensitizes glioblastoma cells
to histone deacetylase inhibitors. Neuro Oncol. 2011 Aug;13(8):894-903.
Epub 2011 Jun 8. PubMed PMID: 21653597; PubMed Central PMCID:
2: Al-Assar O, Mantoni T, Lunardi S, Kingham G, Helleday T, Brunner TB.
Breast cancer stem-like cells show dominant homologous recombination due
to a larger S-G2 fraction. Cancer Biol Ther. 2011 Jun 15;11(12):1028-35.
Epub 2011 Jun 15. PubMed PMID: 21558789.
3: 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.
4: Lopez G, Torres K, Liu J, Hernandez B, Young E, Belousov R, Bolshakov
S, Lazar AJ, Slopis JM, McCutcheon IE, McConkey D, Lev D. Autophagic
survival in resistance to histone deacetylase inhibitors: novel
strategies to treat malignant peripheral nerve sheath tumors. Cancer
Res. 2011 Jan 1;71(1):185-96. Epub 2010 Nov 16. PubMed PMID: 21084276;
PubMed Central PMCID: PMC3064267.
5: 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. Epub 2010 May 12. PubMed PMID:
6: Rivera-Del Valle N, Gao S, Miller CP, Fulbright J, Gonzales C,
Sirisawad M, Steggerda S, Wheler J, Balasubramanian S, Chandra J.
PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity
and Histone Alterations via Caspase-8 and FADD in Leukemia Cells. Int J
Cell Biol. 2010;2010:207420. Epub 2010 Jan 18. PubMed PMID: 20145726;
PubMed Central PMCID: PMC2817379.
7: Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase
inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol.
2010 Feb 4;3:5. Review. PubMed PMID: 20132536; PubMed Central PMCID:
8: Bhalla S, Balasubramanian S, David K, Sirisawad M, Buggy J, Mauro L,
Prachand S, Miller R, Gordon LI, Evens AM. PCI-24781 induces caspase and
reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms
and is synergistic with bortezomib in lymphoma cells. Clin Cancer Res.
2009 May 15;15(10):3354-65. Epub 2009 May 5. Erratum in: Clin Cancer
Res. 2009 Jul 15;15(14):4784-5. PubMed PMID: 19417023; PubMed Central
9: Lopez G, Liu J, Ren W, Wei W, Wang S, Lahat G, Zhu QS, Bornmann WG,
McConkey DJ, Pollock RE, Lev DC. Combining PCI-24781, a novel histone
deacetylase inhibitor, with chemotherapy for the treatment of soft
tissue sarcoma. Clin Cancer Res. 2009 May 15;15(10):3472-83. Epub 2009
May 5. PubMed PMID: 19417021.
10: Adimoolam S, Sirisawad M, Chen J, Thiemann P, Ford JM, Buggy JJ.
HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits
homologous recombination. Proc Natl Acad Sci U S A. 2007 Dec
4;104(49):19482-7. Epub 2007 Nov 27. PubMed PMID: 18042714; PubMed
Central PMCID: PMC2148315.
11: Banuelos CA, Banáth JP, MacPhail SH, Zhao J, Reitsema T, Olive PL.
Radiosensitization by the histone deacetylase inhibitor PCI-24781. Clin
Cancer Res. 2007 Nov 15;13(22 Pt 1):6816-26. PubMed PMID: 18006784.
12: Buggy JJ, Cao ZA, Bass KE, Verner E, Balasubramanian S, Liu L,
Schultz BE, Young PR, Dalrymple SA. CRA-024781: a novel synthetic
inhibitor of histone deacetylase enzymes with antitumor activity in
vitro and in vivo. Mol Cancer Ther. 2006 May;5(5):1309-17. PubMed PMID:
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