Abstract B57: Non-peptide macrocyclic histone deacetylase inhibitors: A structure activity relationship study

Histone deacetylase (HDAC) inhibition is a promising therapeutic strategy for cancer treatment because HDAC inhibitors have shown the ability to arrest proliferation of nearly all transformed cell lines. Recently, we have reported a new class of hydroxamic acid based HDAC inhibitors containing 14- or 15-membered non-peptide macrolide antibiotic (azithromycin, clarithromycin, and TE-802) skeletons as surface recognition group. In these HDAC inhibitors, the modified macrolide antibiotic is linked to the zinc chelating hydroxamic acid moiety via 5- or 6-methylene chain linker. All the compounds showed low nano-molar HDAC inhibitory activities and they selectively inhibited the growth of both small cell and non-small cell lung cancer cells over the healthy cells at concentrations more than 5 times the IC50 values. Azithromycin-linked hydroxamic acids selectively accumulate in vivo in the lung tissues of Bald/C mice, allowing for tissue targeted anti-cancer therapy. To further understand the depth of the SAR of this class of HDAC inhibitors on HDAC inhibitory activities and HDAC isoform selectivity, we investigated the consequence of incorporation of varied methylene-linkers, newly modified macrolide antibiotic skeleton, and new macrocyclic skeleton. We observed that these compounds retain anti-HDAC, anti-proliferative activities and in some cases therapeutic profile is even better than previously reported compounds. Citation Format: Subhasish Tapadar, Idris Raji, Shaghayegh Fathi, Celinah Mwakwari, Eric Raftery, Adegboyega K. Oyelere. Non-peptide macrocyclic histone deacetylase inhibitors: A structure activity relationship study. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B57.