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Max Planck chemists develop novel substance with unique inhibition mode targeting the unfolded protein response highjacked by cancer cells
Cancer cells are pretty bold and clever - they highjack cellular survival and healing processes in order to fuel their grow, spread throughout the body, and ensure their own survival. The unfolded protein response (UPR), that protects cells against stress, is such a pro-survival mechanism. One of its key regulators, the inositol-requiring enzyme 1 (IRE1), has emerged as a promising target for developing therapies against cancer and a variety of other severe diseases. Now, a research team at the Max Planck Institute of Molecular Physiology in Dortmund, led by Peng Wu, has developed a novel substance that inhibits IRE1 through a mechanism distinct from that of already existing inhibitors. This could open new therapeutic avenues for treating cancer and other human diseases.
The laundry is still undone, the bicycle needs fixing, and bills haven’t been paid yet either. Unfinished tasks cause stress. The same principle applies to our cells. When too many proteins are incorrectly or even mis-folded, they cannot perform their functions and the cell becomes stressed. To cope with such stress, cells have evolved the unfolded protein response (UPR). Once activated by stress in the endoplasmic reticulum (ER) - the protein-producing organelle in the cell - a cascade of protective mechanisms is triggered to restore proper protein folding. One of the most important UPR transducers is IRE1, a protein embedded in the ER membrane. IRE1 is involved in a wide range of diseases, including immune, metabolic, and neuro-degenerative disorders as well as cancer and has thus become a relevant therapeutic target.
Cancer cells live under constant stress - intentionally
Tumours are often described as “wounds that never heal”. This is also due to the fact that cancer cells create a toxic environment, that is acidic, hypoxic and nutrient-deprived. Although this seems counter-productive, it is actually a clever strategy: the hostile-conditions activate evolutionary survival pathways, highjacked and repurposed to support tumour growth and survival. “It is well known, that the activation of the UPR via IRE1 contributes to the development and progression of most cancers, such as leukemia, glioblastoma, myeloma, breast, and colon cancer. High IRE1 activity is also associated with increasingly poor prognosis”, says Peng Wu. Over the past decade, signalling proteins of the UPR have become attractive targets for the development of novel cancer therapies, and a growing toolbox of drug-like molecules is now available. However, many of these compounds have limitations.
A new inhibitory mechanism – binding here, inhibiting there
Wu’s group has now developed a high-potency IRE1 inhibitor with a unique inhibition mode. First, the researchers developed a robust assay to evaluate the effect of potential IRE1 inhibitors. Using this assay, they screened a library of 10,000 chemically diverse compounds and identified indole-based scaffolds as particularly promising “hits”. Systematic structural optimisation yielded a lead compound that was then characterized biochemically, biophysically, and by its interaction with IRE1. This revealed its unique inhibition mode: instead of inhibiting one of the two catalytic sites (the kinase or the RNAse domain) by binding to it, the compound binds to the kinase pocket, and through this interaction, allosterically supresses the RNAse activity that drives the UPR. In other words, the compound “binds here, but inhibits there”.
New therapeutic opportunities
Our understanding of the unfolded protein response has steadily evolved over the past few decades, and the first drug-like molecules targeting this process have shown promise in preclinical disease models. Yet many of the existing agents suffer from poor pharmacokinetics and cause significant side effects - particularly pancreatic toxicity. It is suspected that certain reactive moieties in these compounds interfere with cellular processes unrelated to IRE1 activity. Furthermore, some inhibitory mechanisms are not yet fully understood. “Structural und functional studies such as ours, which clearly demonstrate the mechanism of action, are of great value and will accelerate the development of next-generation IRE1 inhibitors”, says Wu. Such compounds could also serve as research tools to determine which approach to fighting cancer is most suitable in clinical practice and which diseases in humans can be treated most effectively by targeting the unfolded protein response.
Liu Y, Goebel L, Avathan Veettil AK, Gasper R, Jian M, Wagner L, Hastürk O, Wu P (2025). Harnessing Indole Scaffolds to Identify Small-molecule IRE1α Inhibitors Modulating XBP1 mRNA Splicing. Nat Commun.
Doi: 10.1038/s41467-025-64291-4
https://www.nature.com/articles/s41467-025-64291-4
https://www.mpi-dortmund.mpg.de/news/disrupting-stress-management-in-cancer-cell...
Cancer cells (purple cell) use cellular survival mechanisms such as UPR to cope with stress. An inhi ...
Source: MPI of Molecular Physiology
Copyright: MPI of Molecular Physiology
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