Chemical probes for the identification of the molecular targets of honokiol

• Published in: European journal of medicinal chemistry 2025-02, Vol.283, p.117102, Article 117102
• Main Authors: Vázquez-Villa, Henar, Rueda-Zubiaurre, Ainoa, Fernández, Daniel, Foronda, Román, Parker, Christopher G., Cravatt, Benjamin F., Martín-Fontecha, Mar, Ortega-Gutiérrez, Silvia
• Format: Article
• Language: English
• Subjects: Allyl Compounds; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biphenyl Compounds - antagonists & inhibitors; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cell Line, Tumor; Chemical probes; Chemical proteomics; Dose-Response Relationship, Drug; Honokiol; Humans; Lignans - chemical synthesis; Lignans - chemistry; Lignans - pharmacology; Molecular Probes - chemical synthesis; Molecular Probes - chemistry; Molecular Probes - pharmacology; Molecular Structure; Phenols; Photoaffinity labeling; Proteomics; Structure-Activity Relationship; Target identification
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.117102

Honokiol is a natural product with an interesting array of biological effects, including significant anti-tumor properties. However, full exploration of its therapeutic potential is hampered by its modest pharmacokinetic profile and by the lack of synthetic methods that allow to obtain specifically designed derivatives with improved properties. In addition, the specific molecular targets of honokiol remain poorly understood, a fact that limits the search of alternative hits for subsequent optimization programs. In this work we describe an optimized series of synthetic routes that allow to access to a variety of honokiol derivatives, including a set of minimalist photoaffinity probes to map potential protein targets in live cells. Chemical proteomic studies of the most potent probe revealed a defined set of proteins as the cellular targets of honokiol. Significantly, up to the 62 % of the identified proteins have described roles in cancer, highlighting their potential relationship with the antitumor effects of honokiol. Furthermore, several of the top hits have been validated as direct binding partners of honokiol by cellular thermal shift assay (CETSA). In sum, the work described herein provides the first landscape of the cellular targets of honokiol in living cells and contributes to define the specific molecular pathways affected by this natural product. [Display omitted] •Synthetic routes for obtaining a variety of honokiol derivatives are described.•New honokiol-based probes suitable for chemical proteomics are reported.•The landscape of the cellular targets of honokiol in living cells is described.•Some of the identified proteins have been validated as honokiol bona-fide targets.