Abstract 2525: Identification and characterization of class I HDAC-specific small-molecule inhibitors with a novel pharmacophore

Abstract

Abstract Small-molecule inhibitors of HDACs (HDIs) have therapeutic potentials for treating cancer, metabolic disorders, cardiovascular diseases and neurodegenerative maladies. Two FDA-approved HDIs (vorinostat and romidepsin) are in clinical use for cancer therapy and a variety of other HDIs have been actively tested in clinical trials. Current challenges facing drug development of HDIs include the lack of isoform specificity, undesirable toxicity and suboptimal therapeutic efficacy against solid tumors. Most HDIs in preclinical or clinical evaluations belong to the hydroxamic acid or aminobenzamide classes. The former class lacks isoform specificity and the latter has not yet been approved for clinical use. Thus, the identification of HDIs with novel chemical properties and isoform-specificity may unleash the considerable therapeutic potential of targeting HDACs. We have conducted a high-throughput screening of >620,000 compounds and identified a lead with a hitherto undescribed pharmacophore with an inhibitory specificity against the class I HDACs, and a low two-digit nanomolar potency. An array of synthetic analogs established the structure-activity relationship. These novel inhibitors induced histone hyperacetylation, suppressed cancer cell proliferation of diverse cancer cell lines including the NCI-60 panel, and malignant cell-biological features associated with tumor metastasis. These compounds are under active preclinical development for cancer therapy. Citation Format: Yunfei Wang, Ryan Stowe, Christie E. Pinello, Lisa Y. Zhao, Guimei Tian, Peter Hodder, William R. Roush, Daiqing Liao. Identification and characterization of class I HDAC-specific small-molecule inhibitors with a novel pharmacophore. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2525. doi:10.1158/1538-7445.AM2014-2525