J Med Chem: enhanced anticancer compounds allow precise activation and tracking of treatment

May 17, 2019 / BIOON / - researchers at the Westar Institute and the University of South Florida have developed a new compound that can be specifically targeted at ER stress Endoplasmic reticulum (ER) stress response is often in a state of hyperactivity in cancer, which can promote the survival of cancer cells under stress This new compound has unique chemical properties, can be precisely activated, and because it can emit fluorescence, it can track its activity in vivo The study was published in Journal of medical chemistry Er is a cell structure that monitors protein folding and assembly, which activates stress response mechanisms to cope with the accumulation of misfolded proteins or other stress conditions, including hypoxia Photo source: Wistar Institute "some cancers rely on the protective effect of ER stress response to maintain their growth in a stressed environment," said Dr Chih Chi Andrew Hu, team leader, immunology, microenvironment and metastasis project, Westar Institute "We and other research groups have shown that targeting er from genes and drugs is a very effective way to treat a variety of tumors "Hu laboratory has been actively promoting a research project of compound development to block the important functions of ER stress response, especially the inhibition of IRE1 protein, which senses ER stress and reacts by activating a series of cell events In addition to inducing apoptosis of tumor cells, these compounds can also activate anti-tumor T cell function, inhibit tumor related immunosuppressive cells, and cause tumor shrinkage in mice "These inhibitors have shown promise in the treatment of several cancers, including chronic lymphocytic leukemia and Burkitt's lymphoma," Hu said Therefore, we are very interested in extending them to clinical practice "In this study, Hu and his collaborators created a molecule called pc-d-f07 through a series of chemical modifications This molecule is not active in pharmacology and needs to be turned on ultraviolet radiation and converted into active d-f07, which is a very effective ire-1 functional inhibitor The new prodrug strategy improves the efficacy of ire-1 inhibitors and allows fine control of their activity at precise times and locations by ultraviolet irradiation Importantly, once activated, d-f07 will emit fluorescence, which can be tracked in cells and in vivo to provide real-time treatment monitoring The new strategy of stimulation mediated drug activity release provides a promising platform for ER stress response targeting anticancer therapy and the development of other effective inhibitors Reference: Chih Chi Andrew Hu et al Structural tailing of a new fluent ire-1 RNase investor to accurately control its activity, Journal of Medical Chemistry (2019) Https://pubs.acs.org.ccindex.cn/doi/10.1021/acs.jmedchem.9b00269