Development of class IIa selective histone deacetylase inhibitors with chemosensitizing properties as anticancer agents

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Histone deacetylases (HDACs) are important enzymes in epigenetic modulation of cells. Their importance in cancer development and treatment is accepted as seen by the approval of 4 HDAC inhibitors (HDACi). Approved HDACi are mostly broad spectrum HDACi which may account for observed severe side effects. Epigenetic drug discovery is thus in part shifting towards the development of class- and isoform-selective HDACi. Research activities of the Kurz and the Kassack laboratories have resulted in the development of HDACi with in vitro anticancer activity and class IIa preference. LMK235 is a class IIa preferential HDACi able to revert chemoresistance in cisplatin-resistant cancer cell lines due to synergistic activity with cisplatin. Furthermore, LMK235 prevents the development of cisplatin resistance in an ovarian cancer cell line. Thus, our working hypothesis is that class IIa HDACs are promising targets for the treatment of specific types of cancer expressing class IIa HDACs such as colon and head neck cancers. The objective of this grant proposal is to develop potent and selective class IIa HDACi and to evaluate their anticancer potential. The question will be addressed whether inhibition of class IIa HDACs is responsible for the anticancer effects of LMK235 observed in previous studies and if such inhibition can serve as a suitable strategy to increase sensitivity of DNA-targeting drugs such as platinum compounds and to prevent the development of resistance. Established strategies of medicinal chemistry will be used for the stepwise improvement of LMK235s class IIa preference over class IIb HDAC isoforms and to improve the already good selectivity over class I HDACs. In order to accomplish both goals, we intend to target the highly conserved catalytic site of class IIa HDACs. The development of class IIa selective HDACi will be guided by molecular docking. Synthesis and structural elucidation will be performed in the group of Prof. T. Kurz. New compounds from the Kurz lab will undergo biological evaluation for HDAC inhibition and anticancer effects in the group of Prof. M. Kassack. Reference HDACi are used for comparison. Compounds will be evaluated in head-neck and colon cancer cell lines for cytotoxicity, effects on cellular HDACs, induction of apoptosis, cell cycle arrest, changes in gene expression and in the acetylation status of HDAC target proteins. Non-cancer cells serve as selectivity controls. Further, enzymatic HDAC assays will be applied to explore the HDAC selectivity profile of the synthesized compounds. Then, compounds are tested for reversal and prevention of chemoresistance against DNA-damaging agents. Underlying molecular mechanism will be explored. In conclusion, this joint research project will yield insight into the so far little known contribution of class IIa HDACs to cancer development and their use as anticancer targets. Furthermore, this project will provide selective class IIa HDAC inhibitors as pharmacological tools.