Scientists at the Wistar Institute and the University of South Florida have advanced a novel compound that specifically targets the endoplasmic reticulum (ER) stress response that is frequently hyperactivated in cancer and promotes survival of cancer cells during stressful conditions. The molecule has unique chemical properties that allow for precise activation and can be used for tracking its activity in vivo thanks to the emission of fluorescence, according to the researchers whose study (“Structural tailoring of a novel fluorescent IRE-1 RNase inhibitor to precisely control its activity”) appears online in the Journal of Medicinal Chemistry.

“Activation of the IRE-1/XBP-1 pathway has been linked to many human diseases. We report a novel fluorescent tricyclic chromenone inhibitor, D-F07, in which we incorporated a 9-methoxy group onto the chromenone core to enhance its potency and masked the aldehyde to achieve long-term efficacy. Protection of the aldehyde as a 1,3-dioxane acetal led to strong fluorescence emitted by the coumarin chromophore, enabling D-F07 to be tracked inside the cell,” the investigators wrote.

“We installed a photo-labile structural cage on the hydroxy group of D-F07 to generate PC-D-F07. Such a modification significantly stabilized the 1,3-dioxane acetal protecting group, allowing for specific stimulus-mediated control of inhibitory activity. Upon photoactivation, the re-exposed hydroxy group on D-F07 triggered the aldehyde-protecting 1,3-dioxane acetal to slowly decompose, leading to the inhibition of the RNase activity of IRE-1. Our novel findings will also allow for spatiotemporal control of the inhibitory effect of other salicylaldehyde-based compounds currently in development.”

The ER is a cellular structure that oversees protein folding and assembly, and it activates stress response mechanisms in response to the accumulation of misfolded proteins or other stressful conditions, including low oxygen.

Chih-Chi Andrew H
Chih-Chi Andrew Hu, PhD

“Certain cancers rely on the protective role of the ER stress response to sustain their growth in stressful environmental conditions,” said Chih-Chi Andrew Hu, PhD, associate professor in Wistar’s immunology, microenvironment & metastasis program, and co-lead author on the study with Juan R. Del Valle, PhD, associate professor of chemistry at the University of South Florida. “We and other groups showed that genetically and pharmacologically targeting the ER is a very effective way to attack various tumors.”

The Hu lab has been actively advancing a research program for the development of compounds to block vital functions of the ER stress response, specifically inhibitors of the IRE1 protein that senses the ER stress and responds by activating a cascade of cellular events. In addition to inducing tumor cell apoptosis, these compounds activate antitumor T-cell function and inhibit tumor-associated immunosuppressive cells in vivo in mouse models, resulting in tumor shrinkage.

“This class of inhibitors has shown therapeutic promise in several cancer types, including chronic lymphocytic leukemia and Burkitt lymphoma,” said Hu. “Therefore, we are very interested in advancing them to the clinic.”

In this study, through a series of chemical modifications, Hu and collaborators created a molecule called PC-D-F07 that is pharmacologically inactive and requires UV irradiation to be “turned on” and converted into the active D-F07, which is a potent inhibitor of IRE-1 function.

The prodrug strategy enhances the efficacy of IRE-1 inhibitors and allows fine control of their activity at a precise time and location by UV irradiation. Once active, D-F07 emits fluorescence that can be tracked in cells and potentially in vivo, providing a real-time therapy readout.

This new strategy for stimulus-mediated release of pharmacological activity provides a promising platform to target the ER stress response for anticancer therapy and for developing other potent inhibitors, say the researchers.

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