The Development Of 19-Substituted Benzoquinone Ansamycins As Potential Anticancer Drugs

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Benzoquinone ansamycins (BQA's) were the first class of Hsp90 inhibitors developed but the use of the prototype agent geldanamycin was limited by hepatotoxicity. One major mechanism of toxicity of the BQA class is manifested via the electrophilic properties of the quinone and alkylation of cellular nucleophiles at the 19-position. We developed novel 19-substituted BQA's in the geldanamycin (GA), 17-AAG and 17-DMAG series as a means to prevent arylation of cellular nucleophiles. 19-substituted BQA's inhibited recombinant Hsp90 and did not react with thiols at the 19-position while marked thiol reactivity could be detected using their parent quinones. We examined the effects of different substitution patterns at the 19-position on the ability of BQAs to inhibit Hsp90 and induce growth inhibitory effects in breast cancer cell lines. We found that both 19-phenyl and 19-methyl BQA's in the 17-AAG, 17-DMAG and GA series were effective inhibitors of purified Hsp90 as demonstrated using an ATPase assay particularly in the presence of NQO1 to generate the hydroquinone ansamycin. Only 19-phenyl substituted BQAs were effective growth inhibitory agents in breast cancer cell lines using an MTT assay while 19-methyl substituted BQAs in the GA, 17-AAG and 17-DMAG series demonstrated only modest growth inhibition. The growth inhibitory effects of 19-phenyl BQAs were potentiated in cells containing high NQO1. Notably, 19-phenyl DMAG had similar growth inhibitory and apoptotic effects as its parent quinone, DMAG. These data demonstrate that the 19-phenyl BQAs had marked growth inhibitory, apoptotic, and client protein expression effect in breast cancer cells compared to 19-methyl BQAs (Supported by CA 51210). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2769. doi:1538-7445.AM2012-2769