(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

Abstract

C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (-)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2-and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis.In addition, central and peripheral administration of (+)-UB006 or (-)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (-)-UB006 that has no anorexigenic side effects.

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…The first is the synthetic compound C75, a weak irreversible FAS inhibitor with an IC 50 between 200-500 μM (racemic mixture). [98][99][100] C75 interacts with FAS in different domains, specifically with KS, TE, and ER domains, 101 and shows anticancer activity in many cancer cell lines and xenograft models. 102,103 However, in vivo studies showed that C75 has a negative side effect: it reduces food intake and induces body weight loss.…”

“…With these results, Makowski et al developed a series of C75-based inhibitors, taking into account the enantiomeric selectivity of FAS. 100,107 They found that elongation of the aliphatic chain or the introduction of larger groups in the β-position of the lactone cause a decrease in inhibitory activity of FAS. 107 This reduced structure-activity relationship study led to the development of a better FAS inhibitor, the (-)-UB006 (20, Figure 4) with an IC 50 of 220 µM for FAS from rat.…”

“…107 This reduced structure-activity relationship study led to the development of a better FAS inhibitor, the (-)-UB006 (20, Figure 4) with an IC 50 of 220 µM for FAS from rat. 100 In vitro studies showed that (-)-UB006 is more cytotoxic than C75 against several cancer cells. Specifically, against the OVCAR3 cell line, it was found to be 40 times more cytotoxic than C75.…”

“…They found that elongation of the aliphatic chain or the introduction of larger groups in the β‐position of the lactone cause a decrease in inhibitory activity of FAS 107 . This reduced structure‐activity relationship study led to the development of a better FAS inhibitor, the (–)‐UB006 ( 20 , Figure 4) with an IC 50 of 220 µM for FAS from rat 100 . In vitro studies showed that (–)‐UB006 is more cytotoxic than C75 against several cancer cells.…”

Identification of novel antilipogenic agents targeting fatty acid biosynthesis through structure‐based virtual screening

“…Indeed, the pharmacological inhibition of FAS has been shown to mediate profound fat mass loss in rodents . The development of FAS inhibitors to combat cancer has been also investigated, in particular against breast cancer, pancreatic cancer, colon cancer, ovarian cancer . Several inhibitors such as orlistat have been designed to target the TE domain using virtual screening or hybrid compounds .…”