A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum
ABSTRACT The discovery of the rules governing the inhibition of the various HDAC isoforms is likely to be key to identifying improved therapeutics that act as epigenetic modulators of gene transcription. Herein we present results on the modification of the CAP region of a set of triazolylphenyl-based HDACIs, and show that the nature of substitution on the phenyl ring plays a role in their selectivity for HDAC1 versus HDAC6, with low to moderate selectivity (2-51-fold) being achieved. In light of the valuable selectivity and potency that were identified for the triazolylphenyl ligand 6b in the inhibition of HDAC6 (IC50 = 1.9 nM), this compound represents a valuable research tool and a candidate for further chemical modifications. Lastly, these new HDACIs were studied for both their anticancer and antimalarial activity, which serve to validate the superior activity of the HDACI 10c.
Drug Design, Development and Therapy 01/2015; DOI:10.2147/DDDT.S56038 · 3.03 Impact Factor
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ABSTRACT: Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and specific physiological roles. Indeed, HDAC6 deacetylates various substrates including α-tubulin and HSP90α, and is involved in protein trafficking and degradation, cell shape and migration. Consequently, deregulation of HDAC6 activity was associated to a variety of diseases including cancer, neurodegenerative diseases and pathological autoimmune response. Therefore, HDAC6 represents an interesting potential therapeutic target. In this review, we discuss structural features of this histone deacetylase, regulation of its expression and activity, biological functions, implication in human disease initiation and progression. Finally will describe novel and selective HDAC6 inhibitors.Epigenomics 02/2015; 7(1):103-18. DOI:10.2217/epi.14.69 · 5.22 Impact Factor
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ABSTRACT: HDACs are one of the most promising drug targets for cancer therapy, and since more than 90% of all cancer-related deaths are associated with tumor metastasis, therefore developing strategies to inhibit tumor metastasis while retaining antitumor growth activity are of great interest. Herein we demonstrated the design and identification of a series of novel hydroxamate-based HDAC inhibitors bearing potent activities against tumor growth and metastasis. Optimization of the initial hit resulted in the discovery of new HDAC inhibitors through studying the SAR. Among them, compound 11b, one of the most potent leads, exhibited nanomolar IC50 values towards inhibition of Class I and IIb HDACs as well as submicromolar activity against proliferation and migration of breast cancer cells in vitro. More importantly, it also significantly suppressed tumor growth in a breast tumor xenograft mouse model and dose-dependently blocked in vivo tumor metastasis in a mouse pulmonary metastasis model.Journal of Medicinal Chemistry 10/2014; 57(22). DOI:10.1021/jm5012148 · 5.48 Impact Factor