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AR-42



Arno is also developing AR-42 (formerly known as "HDAC-42"), an orally available, broad spectrum inhibitor of both histone and non-histone deacetylation proteins ("pan-DAC"), which may both be important in cancer progression. Histone deacetylase ("HDAC") inhibitors are a growing class of compounds that target histone deactylase, a molecule involved in determining which genes are expressed in a particular cell. This class has two approved agents, vorinostat ("SAHA," or Zolinza® by Merck) and romidepsin (Istodax®, Celgene) . In preclinical studies, AR-42 has shown increased potency compared to SAHA, activity against a broad spectrum of deacetylation targets, and unique mechanisms for killing tumor-forming cancer stem cells (Hassane, et al). Recently published preclinical research done in the lab of of John Byrd, MD at the Ohio State University demonstrated the in vitro and in vivo efficacy of AR-42 against B-cell malignancites at tolerable doses, and these results also suggested that AR-42 has greater efficacy in vitro as well as in vivo compared to vorinostat (Lucas, et al). This combination of activity and potency may provide for a toxicity and efficacy profile that differentiates AR-42 from other HDAC inhibitors in this emerging class of compounds.

Arno is currently enrolling an investigator-initiated Phase I/IIa study with AR-42 in collaboration with The Ohio State University in adult patients with relapsed or refractory multiple myeloma (MM), chronic lymphocytic leukemia (CLL) or lymphoma.




Publications

  • Chen CS, Wang YC, Yang HC, Huang PH et al., Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Research, 67:5318-27, 2007.
  • *Chen CS, Weng SC, Tseng PH, Lin HP, and Chen CS. Nonepigenetic effects of histone deacetylase inhibitors on Akt through reshuffling protein phosphatase-1 complexes. J Biol Chem, 280:38879-38887, 2005.
  • *Chen CS, Weng SC, Tseng PH, Lin HP, and Chen CS, Histone Acetylation-independent Effect on Histone Deacetylase Inhibitors on Akt through the Reshuffling of Protein Phosphatase 1 Complexes. Journal of Biological Chemistry November 18, 2005: Volume 280: Number 46.
  • Chen CS, Weng SC, Tseng PH, Lin HP, Chen CS. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem. 2005 Nov 18;280(46):38879-87. Epub 2005 Sep 26.
  • Hassane DC, Balys M, Marcucci G, Byrd JC, Jordan CT, Guzman ML. Identification of the Histone Deacetylase Inhibitor (HDACi),AR-42, as a Novel Anti-Leukemia Stem Cell Agent in Acute Myeloid Leukemia (AML). ASH 2009 Abstract Poster Presentation.
  • Kisseberth WC, Murahari S, London CA, Kulp SK, Chen CS. Evaluation of the effects of histone deacetylase inhibitors on cells from canine cancer cell lines. Am J Vet Res. 2008 Jul;69(7):938-45.
  • Kulp SK, Chen CS, Wang D, Chen CY and Chen CS. Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clinical Cancer Research 12:5199-206, 2006.
  • Lin HY, Chen CS, Lin SP, Weng JR, Chen CS. Targeting histone deacetylase in cancer therapy. Med Res Rev. 2006 Jul;26(4):397-413.
  • Liu S, Wu LC, Pang J, Santhanam R, Schwind S, Wu YZ, Hickey CJ, Yu J, Becker H, Maharry K, Radmacher MD, Li C, Whitman SP, Mishra A, Stauffer N, Eiring AM, Briesewitz R, Baiocchi RA, Chan KK, Paschka P, Caligiuri MA, Byrd JC, Croce CM, Bloomfield CD, Perrotti D, Garzon R, Marcucci G. Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia. Cancer Cell. 2010 Apr 13;17(4):333-47.
  • Lin TY, Fenger J, Murahari S, Bear MD, Kulp SK, Wang D, Chen CS, Kisseberth WC, London CA. AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via downregulation of constitutively activated Kit. Blood. Prepublished online March 16, 2010.
  • Lu Q, Yang YT, Chen CS, Davis M, Byrd JC, Etherton MR, Umar A, Chen CS. Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors. J Med Chem. 2004 Jan 15;47(2):467-74.
  • Lu YS, Kashida Y, Kulp SK, Wang YC et al., Efficacy of OSU-HDAC42, a Novel Histone Deacetylase Inhibitor, in Murine Models of Hepatocellular Carcinoma. Hepatology, Vol. 46, 2007.
  • Lucas DM, Alinari L, West DA, Davis ME, Edwards RB, et al. (2010) The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo. PLoS ONE 5(6): e10941. doi:10.1371/journal.pone.0010941
  • Murahari S, Jalkanen A, Kulp S, Chen CS, Jubala C, Fosmire S, Modiano J, Fossey S, London C, Kisseberth W. OSU-HDAC42, a novel histone deacetylase inhibitor with potent antitumor effects on human and canine osteosarcoma cells. AACR Meeting Abstracts, Apr 2008; 2008: 2445.
  • Sargeant AM, Rengel RC, Kulp SK et al., OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model. Cancer Res 2008; 68: (10).
  • Weng SC, Wu E, Kulp SK, Wang D, Wang YC, Chen CS, Yee LD. The antitumor effects of OSU-HDAC42, a histone deacetylase inhibitor, in HER2-positive breast cancer are mediated partly through Hsp90 modulation. AACR 2009 Abstract.
  • Yang YT, Balch C, Kulp SK, Mand MR, Nephew KP, Chen CS. A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer. Neoplasia. 2009 Jun;11(6):552-63, 3 p following 563.

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