title: First evidence that oligopyridines, α-helix foldamers, inhibit Mcl-1 and sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies.
abstract: Apoptosis control defects such as the deregulation of Bcl-2 family member expression are frequently involved in chemoresistance. In ovarian carcinoma, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect cancer cells against apoptosis and their concomitant inhibition leads to massive apoptosis even in the absence of chemotherapy. Whereas Bcl-xL inhibitors are now available, Mcl-1 inhibition, required to sensitize cells to Bcl-xL-targeting strategies, remains problematic. In this context, we designed and synthesized oligopyridines potentially targeting the Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells, and implemented a functional screening assay to evaluate their ability to sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies. We established structure-activity relationships and focused our attention on MR29072, named Pyridoclax. Surface plasmon resonance assay demonstrated that pyridoclax directly binds to Mcl-1. Without cytotoxic activity when administered as a single agent, pyridoclax induced apoptosis in combination with Bcl-xL-targeting siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cells.
authors.affiliation: Normandie Université , 14032 Caen, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gloaguen
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Voisin-Chiret
authors.forename: Jana
authors.initials: J
authors.lastname: Sopkova-de Oliveira Santos
authors.forename: Jade
authors.initials: J
authors.lastname: Fogha
authors.forename: Fabien
authors.initials: F
authors.lastname: Gautier
authors.forename: Marcella
authors.initials: M
authors.lastname: De Giorgi
authors.forename: Grégory
authors.initials: G
authors.lastname: Burzicki
authors.forename: Serge
authors.initials: S
authors.lastname: Perato
authors.forename: Cécile
authors.initials: C
authors.lastname: Pétigny-Lechartier
authors.forename: Karin
authors.initials: K
authors.lastname: Simonin-Le Jeune
authors.forename: Emilie
authors.initials: E
authors.lastname: Brotin
authors.forename: Didier
authors.initials: D
authors.lastname: Goux
authors.forename: Monique
authors.initials: M
authors.lastname: N'Diaye
authors.forename: Bernard
authors.initials: B
authors.lastname: Lambert
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Louis
authors.forename: Laetitia
authors.initials: L
authors.lastname: Ligat
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lopez
authors.forename: Philippe
authors.initials: P
authors.lastname: Juin
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: Laurent
authors.initials: L
authors.lastname: Poulain
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011725:Pyridines; D051020:bcl-X Protein