MedKoo product information:

AR-42

Descriptin of AR-42: AR-42 is an orally available, broad-spectrum deactylation inhibitor of both histone and non-histone proteins which play an important role in the regulation of gene expression, cell growth and survival. In preclinical studies, AR-42 has demonstrated greater potency and activity in solid and liquid tumors when compared to vorinostat (also known as SAHA and marketed as Zolinza® by Merck) and other deacetylase inhibitors. These data demonstrate the potent and differentiating activity of AR-42. Additionally, pre-clinical findings showed that AR-42 potently and selectively inhibits leukemic stem cells in acute myeloid leukemia, or AML. AR-42 is currently being studied in an investigator-initiated Phase I/IIa clinical study in adult patients with relapsed or refractory multiple myeloma, chronic lymphocytic leukemia or lymphoma.

Current developer:  Arno Therapeutics, Inc.

 AR-42 is a novel class I and II DAC inhibitor that has shown pre-clinical activity in a variety of solid tumor in vitro and in vivo models. (S)-HDAC-42 is a potent orally bioavailable inhibitor of HDAC, as well as targets regulating multiple aspects of cancer cell survival, which might have clinical value in prostate cancer chemotherapy and warrants further investigation in this regard. (source: Clin Cancer Res. 2006 Sep 1;12(17):5199-206.).

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. (source: Arno Therapeutics, Inc., webpages: http://www.arnothera.com/ar42.html).

Highlight on recent research using AR-42

Data published in 2011

AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells. Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM [source: Int J Cancer. 2011 Jul 1;129(1):204-13. doi: 10.1002/ijc.25660. Epub 2010 Dec 1. The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells.
Zhang S, Suvannasankha A, Crean CD, White VL, Chen CS, Farag SS. Division of Hematology and Oncology, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN; Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN.]

Data published in 2010

AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo.

BACKGROUND:  While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.

PRINCIPAL FINDINGS:  In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity. CONCLUSIONS/SIGNIFICANCE:  Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies. [source: PLoS One. 2010 Jun 3;5(6):e10941. The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo. Lucas DM, Alinari L, West DA, Davis ME, Edwards RB, Johnson AJ, Blum KA, Hofmeister CC, Freitas MA, Parthun MR, Wang D, Lehman A, Zhang X, Jarjoura D, Kulp SK, Croce CM, Grever MR, Chen CS, Baiocchi RA, Byrd JC. Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.].

Data published in 2010

AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Histone hypoacetylation occurs in many cancers and inhibition of histone deacetylation is a promising approach to modulate these epigenetic changes. Our laboratory previously demonstrated that the histone deacetylase inhibitors (HDACis) vorinostat and AR-42 reduced the viability of a canine malignant mast cell line. The purpose of this study was to further investigate the mechanisms of pan-HDAC inhibition in normal and malignant mast cells. Mouse and canine malignant mast cell lines expressing various Kit mutations, normal canine mast cells, and primary canine malignant mast cells were treated with AR-42 (a novel HDACi) and effects on cell viability, cycling, and signaling were evaluated. Treatment with AR-42 induced growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7. AR-42 promoted hyperacetylation of H3, H4, and alpha-tubulin, and up-regulation of p21. Down-regulation of Kit occurred after AR-42 treatment via inhibition of Kit transcription. Disassociation between Kit and heat shock protein 90 (HSP90) and up-regulation of HSP70 were observed after AR-42 treatment, suggesting potential loss of HSP90 chaperone function. Lastly, AR-42 down-regulated the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. In summary, AR-42 exhibits in vitro and ex vivo biologic activity against malignant mast cells, representing a promising therapeutic approach for malignant mast cell disease. [source: Blood. 2010 May 27;115(21):4217-25. Epub 2010 Mar 16. AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Lin TY, Fenger J, Murahari S, Bear MD, Kulp SK, Wang D, Chen CS, Kisseberth WC, London CA. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.]

References

1: Zhang S, Suvannasankha A, Crean CD, White VL, Chen CS, Farag SS. The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells. Int J Cancer. 2011 Jul 1;129(1):204-13. doi: 10.1002/ijc.25660. Epub 2010 Dec 1. PubMed PMID: 20824695.

2: Lucas DM, Alinari L, West DA, Davis ME, Edwards RB, Johnson AJ, Blum KA, Hofmeister CC, Freitas MA, Parthun MR, Wang D, Lehman A, Zhang X, Jarjoura D, Kulp SK, Croce CM, Grever MR, Chen CS, Baiocchi RA, Byrd JC. The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo. PLoS One. 2010 Jun 3;5(6):e10941. PubMed PMID: 20532179; PubMed Central PMCID: PMC2880605.

3: 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 down-regulation of constitutively activated Kit. Blood. 2010 May 27;115(21):4217-25. Epub 2010 Mar 16. PubMed PMID: 20233974.

4: Stoenner RW, Schaeffer OA, Katcoff S. Half-Lives of Argon-37, Argon-39, and Argon-42. Science. 1965 Jun 4;148(3675):1325-8. PubMed PMID: 17791262.