Institut de Chimie de Nice UMR 7272

Michael Cerezo,1,2,14 Abdelali Lehraiki,1,2,14 Antoine Millet,3,14 Florian Rouaud,1,2 Magali Plaisant,1,2 Emilie Jaune,1,2 Thomas Botton,1,2 Cyril Ronco,3 Patricia Abbe,1,2 Hella Amdouni,3 Thierry Passeron,1,2,4 Veronique Hofman,2,5,6 Baharia Mograbi,2,5 Anne-Sophie Dabert-Gay,2,7 Delphine Debayle,2,7 Damien Alcor,1,2 Nabil Rabhi,8 Jean-Sebastien Annicotte,8 Laurent Heliot,9 Mariano Gonzalez-Pisfil,9 Caroline Robert,10 Solange Morera,11 Armelle Virougoux,11 Philippe Gual,12 Maruf M.U. Ali,13 Corine Bertolotto,1,2,4 Paul Hofman,2,5,6 Robert Ballotti,1,2,4 Rachid Benhida,3, * and Stephane Rocchi1,2,4,*

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1 INSERM, U1065, Equipe Biologie et Pathologie des cellules melanocytaire : de la pigmentation cutanee au melanome, Centre Mediterraneen de Medecine Moleculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestiere, 06204 Nice cedex 3, France
2 UFR de Medecine, Universite de Nice Sophia Antipolis, 06000 Nice, France
3 Institut de Chimie de Nice UMR UNS-CNRS 7272, Universite Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France
4 Service de Dermatologie, Hopital Archet II, CHU, 06204 Nice, France
5 Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Nice 06107, France
6 Laboratoire de pathologie clinique et experimentale et Hospital-related biobank (BB-0033-00025), Hopital Pasteur, 06002 Nice, France
7 CNRS UMR 7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), 06560 Sophia Antipolis, France
8 University Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, 59000 Lille, France
9 Equipe Biophotonique Cellulaire Fonctionnelle, Laboratoire de Physique des Lasers, Atomes et Molecules (PhLAM) GDR 2588, 59658 Villeneuve d’Ascq, France
10 Department of Dermatology, Cancer Campus, Gustave Roussy Institute, 114, rue Edouard-Vaillant, 94805 Villejuif, France
11 Institute for Integrative Biology of the Cell (I2BC), CNRS CEA University Paris-Sud, Universite´ Paris-Saclay, Gif-sur-Yvette 91198, France
12 INSERM, U1065, Team 8, Centre Mediterraneen de Medecine Moleculaire (C3M), 151 route de Saint Antoine de Ginestiere, 06204 Nice cedex 3, France
13 Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
14 Co-first author
*Correspondence : benhida@unice.fr (R.B.), srocchi@unice.fr (S.R.)

Abstract We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on allmelanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified thechaperone BiP/GRP78/HSPA5as thespecific target of HA15 and demonstrated that the interaction increases ER stress, leading tomelanoma cell death by concomitant induction of autophagic and apoptoticmechanisms.