title: Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy.
abstract: Autophagy inhibition is emerging as a promising anticancer strategy. We recently reported that the circadian nuclear receptor REV-ERBβ plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)cyclopentyl]amino]methyl]-2-[(4-methylpiperazin-1-yl)methyl]phenol, 1 (ARN5187), as a novel dual inhibitor of REV-ERBβ and autophagy. 1 had improved cytotoxicity against BT-474 breast cancer cells compared to chloroquine, a clinically relevant autophagy inhibitor. Here, we present the results of structure-activity studies, based around 1, that disclose the first class of dual inhibitors of REV-ERBβ and autophagy. This study led to identification of 18 and 28, which were more effective REV-ERBβ antagonists than 1 and were more cytotoxic to BT-474. The combination of optimal chemical and structural moieties of these analogs generated 30, which elicited 15-fold greater REV-ERBβ inhibitory and cytotoxic activities compared to 1. Furthermore, 30 induced death in a panel of tumor cell lines at doses 5-50 times lower than an equitoxic amount of chloroquine but did not affect the viability of normal mammary epithelial cells.
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Esther
authors.initials: E
authors.lastname: Torrente
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Parodi
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ercolani
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: De Mei
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ferrari
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Grimaldi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C090977:NR1D2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins