Development of Low-Nanomolar Covalent Epoxide Inhibitors of Tubulin Detyrosinating Enzymes VASH1&2
Year: 2025
Type: article
Abstract: The development of small molecule inhibitors targeting the set of microtubules’ post-translational modifications, also known as the “tubulin code”, remains an underexplored area in medicinal chemistry. The recent discovery of the VASH1 and VASH2 enzymes, which are responsible for tubulin detyrosination─a modification associated with neurodegeneration and cancer─prompted us to develop new molecules that inhibit their activity. In this study, we conducted the first QSAR analysis of VASH proteases. Through rational substrate-based design, we identified our lead compound, LV87, as a potent epoxide-based covalent inhibitor of tubulin detyrosination in cellulo. Specificity assessments against other cysteine proteases and incubations with nonspecific nucleophiles demonstrated that LV87 selectively targets VASH1/2. Additionally, safety data, serum, and microsome stability tests support the notion that LV87 is a selective and potent inhibitor of tubulin detyrosination, paving the way for further optimization and applications.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: Infrastructures en Biologie Santé et Agronomie, Institut Carnot Chimie Balard Cirimat, Agence Nationale de la Recherche, Association Nationale de la Recherche et de la Technologie, Association France Alzheimer, Centre National de la Recherche Scientifique, Université de Montpellier, Institut Carnot Santé Animale, Région Occitanie Pyrénées-Méditerranée
OpenAlex ID: W4413510736