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.

A broad-spectrum antibiotic, DCAP, reduces uropathogenic Escherichia coli infection and enhances vorinostat anticancer activity by modulating autophagy

“…With this asset, we screened a subset of small molecules present in the internal chemical collection of the Ististuto Italiano di Tecnologia (Italy), which contains both commercially available and in-house synthetized compounds. Among them, we selected ~200 diverse and non-redundant molecules with structural and chemical features different from current characterized autophagy modulators, including polyamines 24 , quinolones 25 and cyclic-substituted amines 7 , 26 ). This screening revealed that a carbazol-containing compound previously characterized as a broad-spectrum antibiotic, 2-((3-(3, 6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl) amino)-2-(hydroxymethyl) propane-1, 3-diol (DCAP) was a novel autophagy modulator.…”

Autophagy regulation in the development and treatment of breast cancer

“…A recent report on a cell-permeable autophagyinducing peptide, derived from an evolutionally conserved domain of Beclin-1, confirmed its autophagy-inducing role and anti-viral activity in mice. Other types of drugs with an autophagy-inducing effect also possess potential application in cancer treatment [49,51,58,71]. For instance, histone deacetylase (HDAC) inhibitors (givinostat, vorinostat, panobinostat, etc.)…”

Autophagy Modulation for Organelle-Targeting Therapy

“…3-MA does not inhibit BECN1-independent autophagy [29]. -yl)methyl]phenol, 1 is a lysosomotropic compound with a dual inhibitory activity against the circadian regulator NR1D2/REV-ERBβ and autophagy [31,32].…”

“…The sensitizing effects of inhibiting autophagy on the antitumor efficacy of chemotherapeutic agents have been recapitulated in preclinical models of Myc-induced lymphoma [67,149], colon cancer [45,59,127,128,131,145,[150][151][152][153], ovarian cancer [154], breast cancer [31,32,155,156] hepatocellular cancer [157], prostate cancer [148,156], bladder cancer [156], melanoma [114], and glioma [152,158]. Preclinical evidence reveals the efficacy of CQ to inhibit the genesis and self-renewal of cancer stem cells (CSC) and underlines the impact of this "old drug" as repurposing strategy to open a new CSC-targeted chemoprevention era [153].…”