Potent and Selective Non‐hydroxamate Histone Deacetylase 8 Inhibitors. (9th November 2016)

• Record Type: Journal Article
• Authors: Kleinschek, Alexander; Meyners, Christian; Digiorgio, Eros; Brancolini, Claudio; Meyer‐Almes, Franz‐Josef
• Is Part Of: ChemMedChem. Volume 11:Number 23(2016)
• Page Start: 2598
• Page End: 2606
• Publication Date: 2016-11-09
• Subjects: cancer -- drug discovery -- HDAC8 -- histone deacetylase 8 -- inhibitors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600528
• Languages: English
• ISSNs: 1860-7179

Abstract

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 pyrimido[1, 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 pyrimido[1, 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 pyrimido[1, 2‐ c ][1, 3]benzothiazin‐6‐imine scaffold into innovative and highly effective therapeutic drugs against cancer. Abstract : Evading traditional concepts : The pyrimido[1, 2‐ c ][1, 3]benzothiazin‐6‐imine scaffold does not contain any of the common zinc(II) binding groups. Nevertheless, some derivatives of this scaffold show extraordinarily high potency and selectivity against histone deacetylase 8, an important cancer target.