Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 27, Issue 45, Pages 4610-4629Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1381612827666210917143953
Keywords
Histone deacetylases; HDACi; rational drug discovery; structural insights; breast cancer; differential HDAC expression; HDAC-isoform selectivity
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Research on the differential expression of HDAC isoforms in different types of breast cancer cells may lead to the discovery of selective HDAC inhibitors for personalized treatment.
Background: Breast cancer is the most prevalent cancer amongst females across the globe, and with over 2 million new cases reported in 2018, it poses a huge economic burden to the already dwindling public health. A dearth of therapies in the pipeline to treat triple-negative breast cancers and acquisition of resistance against the existing line of treatments urge the need to strategize novel therapeutics in order to add new drugs to the pipeline. HDAC inhibitors (HDACi) is one such class of small molecule inhibitors that target histone deacetylases to bring about chromosomal remodelling and normalize dysregulated gene expression that marks breast cancer progression. Objective: While four HDACi have been approved by the FDA for the treatment of different cancer types, no HDACi is specifically earmarked for clinical management of breast cancer. Owing to the differential HDAC expression pertaining to different types of breast cancers, isoform-selective HDAC inhibitors need to be discovered. Conclusion: This review attempts to set the stage for the rational structure-based discovery of isoform-selective HDACi by providing structural insights into different HDACs and their catalytic folds based on their classes and individual landscape. The development of inhibitors in accordance with the differential expression of HDAC isoforms exhibited in breast cancer cells is a promising strategy to rationally design selective and effective inhibitors, adopting a 'personalized-medicine' approach.
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