largazole and Neoplasms

The labeling of proteins with small ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers regulates a plethora of activities within the cell, such as protein recycling, cell cycle modifications, and protein translocation. These processes are often overactive in diseased cells, leading to unregulated cell growth and disease progression. Therefore, in systems where Ub/Ubl protein labeling is dysregulated, the development of drugs to selectively and potently disrupt Ub/Ubl protein labeling offers a targeted molecular approach for sensitizing these diseased cells. This Perspective outlines the progress that has been made in the context of inhibitor development for targeting Ub/Ubl pathways.

Topics: Animals; Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasms; Ubiquitin; Ubiquitin-Activating Enzymes

Histone acetylation is an extensively investigated post-translational modification that plays an important role as an epigenetic regulator. It is controlled by histone acetyl transferases (HATs) and histone deacetylases (HDACs). The overexpression of HDACs and consequent hypoacetylation of histones have been observed in a variety of different diseases, leading to a recent focus of HDACs as attractive drug targets. The natural product largazole is one of the most potent natural HDAC inhibitors discovered so far and a number of largazole analogs have been prepared to define structural requirements for its HDAC inhibitory activity. However, previous structure-activity relationship studies have heavily investigated the macrocycle region of largazole, while there have been only limited efforts to probe the effect of various zinc-binding groups (ZBGs) on HDAC inhibition. Herein, we prepared a series of largazole analogs with various ZBGs and evaluated their HDAC inhibition and cytotoxicity. While none of the analogs tested were as potent or selective as largazole, the Zn

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Depsipeptides; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Humans; Molecular Docking Simulation; Neoplasms; Structure-Activity Relationship; Thiazoles; Zinc

The synthesis of an isosteric analog of the natural product and HDAC inhibitor largazole is described. The sulfur atom in the thizaole ring of the natural product has been replaced with an oxygen atom, constituting an oxazole ring. The biochemical activity and cytotoxicity of this species is described.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Depsipeptides; Histone Deacetylase Inhibitors; Humans; Molecular Docking Simulation; Neoplasms; Oxazoles; Thiazoles