Potent and Selective Non‐hydroxamate Histone Deacetylase 8 Inhibitors |
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| Authors: | Alexander Kleinschek Christian Meyners Eros Digiorgio Prof?Dr Claudio Brancolini Prof?Dr Franz‐Josef Meyer‐Almes |
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| Affiliation: | 1. Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany;2. Dipartimento di Scienze Mediche e Biologiche, MATI Center of Excellence, Università degli Studi di Udine, Udine, Italy |
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| Abstract: | Specific inhibition of histone deacetylase 8 (HDAC8) has been suggested as a promising option for the treatment of neuroblastoma and T‐cell malignancies. A novel class of highly potent and selective HDAC8 inhibitors with a pyrimido1,2‐c]1,3]benzothiazin‐6‐imine scaffold was studied that is completely different from the traditional concept of HDAC inhibitors comprising a zinc binding group (ZBG), in most cases a hydroxamate group, a spacer, and a capping group that may interact with the surface of the target protein. Although lacking a ZBG, some of the new compounds were shown to have outstanding potency against HDAC8 in the single‐digit nanomolar range. The pyrimido1,2‐c]1,3]benzothiazin‐6‐imines also inhibited the growth of solid and hematological tumor cells. The small size and beneficial physicochemical properties of the novel HDAC inhibitor class underline the high degree of drug likeness. This and the broad structure–activity relationship suggest great potential for the further development of compounds with the pyrimido1,2‐c]1,3]benzothiazin‐6‐imine scaffold into innovative and highly effective therapeutic drugs against cancer. |
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| Keywords: | cancer drug discovery HDAC8 histone deacetylase 8 inhibitors |
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