title: Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737.
abstract: One approach currently being developed in anticancer drug discovery is to search for small compounds capable of occupying and blocking the hydrophobic pocket of anti-apoptotic Bcl-2 family members necessary for interacting with pro-apoptotic proteins. Such an approach led to the discovery of several compounds, such as ABT-737 (which interacts with Bcl-2, Bcl-xl, and Bcl-w) or the latest one, ABT-199, that selectively targets Bcl-2 protein. The efficacy of those compounds is, however, limited by the expression of two other anti-apoptotic Bcl-2 members, Mcl-1 and Bfl-1. Based on the role of Bfl-1 in cancer, especially in chemoresistance associated with its overexpression in B-cell malignancies, we searched for modulators of protein-protein interaction through a high-throughput screening of a designed chemical library with relaxed drug-like properties to identify small molecules targeting Bfl-1 anti-apoptotic protein. We found two compounds that display electrophilic functions, interact with Bfl-1, inhibit Bfl-1 protective activity, and promote cell death of malignant B cells. Of particular interest, we observed a synergistic effect of those compounds with ABT-737 in Bfl-1 overexpressing lymphoma cell lines. Our results provide the basis for the development of Bfl-1 specific antagonists for antitumor therapies.
authors.affiliation: CIRI, Université de Lyon, France; INSERM, U1111, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mathieu
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques in silico, France INSERM UMR-S 973, Paris Cedex 13, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sperandio
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com INSERM U761, Biostructures and Drug Discovery, Université de Lille, Institut Pasteur de Lille, IFR 142, PRIM, Lille, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Pottiez
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier1; Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Balzarin
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com INSERM U761, Biostructures and Drug Discovery, Université de Lille, Institut Pasteur de Lille, IFR 142, PRIM, Lille, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Herlédan
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques in silico, France INSERM UMR-S 973, Paris Cedex 13, France.
authors.forename: Judith O
authors.initials: JO
authors.lastname: Elkaïm
authors.affiliation: Université Lyon 1, Univ Lyon, CNRS, UMR5086, Bases Moléculaires et Structurales des Systèmes Infectieux, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Fogeron
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com INSERM U761, Biostructures and Drug Discovery, Université de Lille, Institut Pasteur de Lille, IFR 142, PRIM, Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Piveteau
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com INSERM U761, Biostructures and Drug Discovery, Université de Lille, Institut Pasteur de Lille, IFR 142, PRIM, Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dassonneville
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com INSERM U761, Biostructures and Drug Discovery, Université de Lille, Institut Pasteur de Lille, IFR 142, PRIM, Lille, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques in silico, France INSERM UMR-S 973, Paris Cedex 13, France.
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.affiliation: CIRI, Université de Lyon, France; INSERM, U1111, Ecole Normale Supérieure de Lyon, Lyon, France IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier1; Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonnefoy
authors.affiliation: CDithem. Faculté de Pharmacie, Lille, France; www.CDithem.com INSERM U761, Biostructures and Drug Discovery, Université de Lille, Institut Pasteur de Lille, IFR 142, PRIM, Lille, France benoit.deprez@univ-lille2.fr bruno.villoutreix@inserm.fr nathalie.bonnefoy@inserm.fr florence.leroux@pasteur-lille.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D004351:Drug Resistance; D005978:Glutathione / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D015778:Minor Histocompatibility Antigens; D008968:Molecular Conformation; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013050:Spectrometry, Fluorescence; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C096816:BCL2-related protein A1; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015778:Minor Histocompatibility Antigens; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D005982:Glutathione Transferase; D005978:Glutathione; C579720:venetoclax
keywords: Bcl-2; Bfl-1; apoptosis; high-throughput screening; protein–protein interaction inhibitors