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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: http://www.pharmacyclics.com/hdac_oncology.html).

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 HDACI PCI-24781 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 PCI-24781 at IC(50) of 0.43 to 2.7. When we looked for synergy of PCI-24781 with chemotherapeutic agents, we found that PCI-24781 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 PCI-24781 in multidrug-resistant sarcoma cell lines. In conclusion, HDACI PCI-24781 synergizes with chemotherapeutic drugs to induce apoptosis and reverses drug resistance in multidrug-resistant sarcoma cell lines. (source: Anticancer Res. 2011 Apr;31(4):1115-23.)

Current developer:  Pharmacyclics Inc.

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: PMC3145466.

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: 20461381.

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: PMC2827364.

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 PMCID: PMC2704489.

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: 16731764.