Histone deacetylase inhibitors with a primary amide zinc binding group display antitumor activity in xenograft model.

Barbara Attenni, Jesus M Ontoria, Jonathan C Cruz, Michael Rowley, Carsten Schultz-Fademrecht, Christian Steinkühler, Philip Jones

IRBM/Merck Research Laboratories, Pomezia, Rome, Italy. thomas_e_barta@yahoo.com

Bioorganic & medicinal chemistry letters 2009 Jun 1

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Histone deacetylase (HDAC) inhibition causes hyperacetylation of histones leading to differentiation, growth arrest and apoptosis of malignant cells, representing a new strategy in cancer therapy. Many of the known HDAC inhibitors (HDACi) that are in clinical trials possess a hydroxamic acid, that is a strong Zn(2+) binding group, thereby inhibiting some of the class I and class II isoforms. Herein we describe the identification of a selective class I HDAC inhibitor bearing a primary carboxamide moiety as zinc binding group. This HDACi displays good antiproliferative activity against multiple cancer cell lines, and demonstrates efficacy in a xenograft model comparable to vorinostat.

Citation

Barbara Attenni, Jesus M Ontoria, Jonathan C Cruz, Michael Rowley, Carsten Schultz-Fademrecht, Christian Steinkühler, Philip Jones. Histone deacetylase inhibitors with a primary amide zinc binding group display antitumor activity in xenograft model. Bioorganic & medicinal chemistry letters. 2009 Jun 1;19(11):3081-4