Abstract
Chimeric compounds combine the structural features of inhibitors of histone deacetylases (HDACi) and tyrosine kinase inhibitors (TKi), and therefore unite the effects of a dual-targeting strategy in one compound. Here, we describe the generation of such hybrid molecules. Small molecules, known as TKi, are combined with a Zn2+ chelating motive, preferentially a hydroxamic acid, in addition. The resulting small molecules also can inhibit histone deacetylases, which are dependent on the catalytically active Zn2+. Moreover, we summarize how the growth-inhibitory effects of these combined compounds can be determined with a simple proliferation assay with a leukemic cell line.
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References
Quintas-Cardama A, Santos FPS, Garcia-Manero G (2011) Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia 25:226–235
Pietschmann K, Buchwald M, Müller S, Knauer SK, Kögl M, Heinzel T, Krämer OH (2012) Differential regulation of PML–RARα stability by the ubiquitin ligases SIAH1/SIAH2 and TRIAD1. Int J Biochem Cell Biol 44:132–138
Schneider G, Krämer OH, Fritsche P, Schüler S, Schmid RM, Saur D (2010) Targeting histone deacetylases in pancreatic ductal adenocarcinoma. J Cell Mol Med 14:1255–1263
Krämer OH, Stauber RH, Bug G, Hartkamp J, Knauer SK (2013) SIAH proteins: critical roles in leukemogenesis. Leukemia 27:792–802
Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L et al (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64:6626–6634
Bali P, George P, Cohen P, Tao J, Guo F, Sigua C et al (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10:4991–4997
Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H et al (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2:971–984
Kraemer OH, Mahboobi S, Sellmer A (2014) Drugging the HDAC6-HSP90 interplay in malignant cells. Trends Pharmacol Sci 35:501–509
Buchwald M, Pietschmann K, Muller JP, Böhmer FD, Heinzel T, Krämer OH et al (2010) Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation. Leukemia 24:1412–1421
Lai C-J, Bao R, Tao X, Wang J, Atoyan R, Qu H et al (2010) CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res 70:3647–3656
Krämer OH (2009) HDAC2: a critical factor in health and disease. Trends Pharmacol Sci 30:647–655
Suzuki T (2009) Explorative study on isoform-selective histone deacetylase inhibitors. Chem Pharm Bull 57:897–906
Hou J, Li Z, Fang Q, Wang J, Atoyan R, Qu H et al (2012) Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead. J Med Chem 55:3066–3075
Cai X, Zhai H-X, Wang J, Forrester J, Qu H, Yin L et al (2010) Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 53:2000–2009
George P, Bali P, Cohen P, Tao J, Guo F, Sigua C et al (2004) Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res 64:3645–3652
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This work was supported by the Deutsche Forschungsgemeinschaft grant # MA 2183/1-1.
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Mahboobi, S., Pilsl, B., Sellmer, A. (2017). Generation and Assessment of Fusions Between HDACi and TKi. In: Krämer, O. (eds) HDAC/HAT Function Assessment and Inhibitor Development. Methods in Molecular Biology, vol 1510. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6527-4_31
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DOI: https://doi.org/10.1007/978-1-4939-6527-4_31
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