Drug Discovery 2022: driving the next life science revolution

Inhibiting Mechanotransduction as a novel approach for Oncology therapy


M Nijaguna1; I Viciano1; A Le Roux1; P Roca-Cusachs1
1 Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain


Most solid tumors display an increase in tissue stiffness, which is known to drive tumor progression. While this fact has clear clinical implications, currently, there are no compounds or drugs available that block mechanotransduction. Our lab has demonstrated that tissue stiffness triggers the unfolding of a mechanosensor target protein, inducing an interaction with its binding partner. This interaction leads to a cascade of events, transmitting the mechanical cues to biochemical signals in a process called mechanotransduction. This process results in the nuclear translocation of a mechanosensitive transcription factor, implicated in the progression of many cancer types. Therefore, blocking the interaction between the target and its binding partner has a major potential as a therapeutic approach in several solid cancer types. Based on this study, we envision a novel approach focused on inhibiting mechanotransduction, which is not a conventional target in oncology therapy. We aim to identify small molecule inhibitors that bind and stabilize the target, prevent its unfolding, and thus block the interaction and subsequent mechanotransduction. We have developed a virtual screening pipeline and a high throughput screening (HTS) assay for hit discovery. The identified and validated hits will be further optimized to lead compounds and tested in stiffness-dependent relevant in vitro and in vivo model systems to delineate the mechanism of action. The outcome of this study will be a first-in-class mechanoinhibitor with therapeutic applications in oncology and various other pathological conditions. Additionally, the identified tool compound would shed light on many fundamental aspects in the mechanobiology research.

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