In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B80-B80
Abstract:
The protein deacetylase HDAC8 has been recognized to be a potential target for the treatment of certain types of cancer, e.g. CNS cancer or T-cell leukemia. Starting out froom HDAC8 inhibitors with potency in the low micromolar region we have prepared a series of analogues and subjected them to iterative cycles of in-vitro testing using a fluorescence based assay and subsequent synthetic variation. Molecular docking to available X-ray structures of human HDAC8 further supported the process. We have obtained potent HDAC8 inhibitors in-vitro (potency down to 26 nM) and high selectivity over hHDAC1 and 6( & gt;200fold). Selected inhibitors block the proliferation of different cancer cell lines in culture (SH-SY5Y glioblastoma, Jurkat T-cell leukemia) and show hyperacetylation (shown by Western blotting) of the HDAC8 target Ac-SMC3. Thus, we have obtained potent and selective HDAC8 inhibitors with cellular activity and target engagement. Mechanistic studies are underway to further optimized selected compounds. Citation Format: Manfred Jung, Alokta Chakrabarti, Tino Heimbach, Wolfgang Sippl, Martin Marek, Christophe Romier, Ina Oehme, Olaf Witt. New inhibitors of histone deacetylase 8 (HDAC8) as anticancer agents. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B80.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-15-B80
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2062135-8
SSG:
12
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