Development of Low-Nanomolar Covalent Epoxide Inhibitors of Tubulin Detyrosinating Enzymes VASH1&2
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 <i>in cellulo</i>. 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.
Authors
- Krzysztof Rogowski (ORCID: https://orcid.org/0000-0002-0206-3289)
- Anthony Feral (ORCID: https://orcid.org/0000-0001-8896-9710)
- Pascal Verdié (ORCID: https://orcid.org/0000-0002-5807-0293)
- Maxime Louet (ORCID: https://orcid.org/0000-0002-5840-2147)
- Aicha Talha (ORCID: https://orcid.org/0000-0001-8250-5333)
- Matthieu Simon (ORCID: https://orcid.org/0000-0002-9202-1583)
- Yoann Lannay (ORCID: https://orcid.org/0009-0006-6472-5088)
- Lubomir Vezenkov (ORCID: https://orcid.org/0000-0001-6348-7985)
- Siem van der Laan (ORCID: https://orcid.org/0000-0001-8169-1963)
- Guillaume Marcellin (ORCID: https://orcid.org/0009-0006-2831-7845)
- Muriel Amblard (ORCID: https://orcid.org/0000-0001-8922-1755)
- Khaled Hached (ORCID: https://orcid.org/0000-0003-1143-6929)
- Yazid Souf (ORCID: https://orcid.org/0000-0002-1717-9137)
- Camille Hennebert
- Aline Haetty
Institutions
- École Nationale Supérieure de Chimie de Montpellier (FR)
- Centre National de la Recherche Scientifique (FR)
- Université de Montpellier (FR)
- Montpellier GenomiX (FR)
- American College of Traditional Chinese Medicine (US)
- Géosciences Montpellier (FR)
- Institut des Biomolécules Max Mousseron (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00980
- Citations
- 3
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.42
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