Development of fluorizoline analogues as prohibitin ligands that modulate C-RAF signaling, p21 expression and melanogenesis.

Nora Chouha, Hussein Abou-Hamdan, Hajime Yurugi, Riku Yoshii, Hiromi Ii, Ahmad Najem, Ghanem E Ghanem, Susumu Nakata, Krishnaraj Rajalingam, Yu Peng, Dong Wang, Canan G Nebigil, Laurent Désaubry

Journal: European journal of medicinal chemistry 2022;242():114635

PMID: 35988448

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Abstract

Fluorizoline is a cytotoxic trifluorothiazoline that targets the scaffold proteins prohibitins-1 and -2 (PHB1/2) to inhibit the kinase C-RAF and promote the expression of the cyclin-dependent kinase inhibitor p21 to induce cancer cell death. In melanocytes, fluorizoline also induces the synthesis of melanin. Herein we report the first structural requirement of fluorizoline analogues for these activities. We identified in particular some compounds that display enhanced anti-C-RAF and anti-MEK activities, and a higher cytotoxicity in HeLa cells compared to fluorizoline. These results provide a foundation for further optimization of PHB ligands for the treatment of cancers. We also discovered an analogue of fluorizoline that displays pharmacological effects opposed to those of fluorizoline and that can be used as a chemical tool to explore PHB signaling in cancers and other diseases.

Address: Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, 1 Rue Eugène Boeckel, 67000, Strasbourg, France; Laboratory of Chemistry and Environmental Chemistry (LCCE), Department of Chemistry, Faculty of Sciences, Batna-1 University, Batna, Algeria.; Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, 1 Rue Eugène Boeckel, 67000, Strasbourg, France.; Cell Biology Unit, University Medical Center Mainz, JGU-Mainz, Germany.; Department of Clinical Oncology, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, Kyoto, 607-8414, Japan.; Laboratory of Oncology and Experimental Surgery (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1070, Anderlecht, Belgium.; Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.; Institute of Materia Medica, Xinjiang University, Urumqi, 830017, Xinjiang, China.; Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, 1 Rue Eugène Boeckel, 67000, Strasbourg, France; Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China. Electronic address: [email protected].

DOI: 10.1016/j.ejmech.2022.114635