Nucleotides play an important role

Nucleotides play an important role in host cell latanoprost mg and are essential for virus infection. Many inhibitors targeting de novo pyrimidine biosynthesis (Fig. 7B) have been well studied on dengue virus, HBV, HEV and other virus infection models (Beardsley et al., 1989; Greene et al., 1995; Hoppe-Seyler et al., 2012; Nelson et al., 1975; Qing et al., 2010; Silva et al., 1997; Wang et al., 2011, 2016b). In this study, we demonstrated that both BQR and LFM, inhibitors of DHODH enzyme, have potent antiviral activity against rotavirus infection. Mechanistic study demonstrated that BQR and LFM exert their anti-rotavirus effect through targeting DHODH to deplete pyrimidine nucleotide pool. Therefore, targeting pyrimidine biosynthesis represents a potential approach for developing antivirals against rotavirus.
Conflicts of interest
Introduction Despite the advance of pathway-targeted therapeutics, KRAS mutant cancers still remain a largely unmet medical need. The prevalence of activating KRAS mutations is particularly high (greater than 90%) in pancreatic ductal adenocarcinoma (Bardeesy and DePinho, 2002), which has a notoriously poor prognosis. KRAS mutations are also prevalent in lung and colon cancers, and the presence of these mutations negatively impacts therapeutic efficacy (Linardou et al., 2008). While direct targeting of the KRAS protein has shown renewed promise (Hunter et al., 2014, Ostrem et al., 2013, Sun et al., 2012), KRAS inhibitors have not yet entered the clinic. Synthetic lethality screens have frequently been used to find alternative points of intervention in mutant KRAS-driven cancers, but the results of these screens have not yet been translated to clinical benefit. Previous synthetic lethal screening efforts (Cox et al., 2014) have mainly used RNAi as a means of identifying potential targets (Barbie et al., 2009, Kim et al., 2016, Luo et al., 2009, Scholl et al., 2009), although a few screens (Shaw et al., 2011, Steckel et al., 2012) have been performed with small chemical libraries. In all cases, these screens have relied on adherent monolayer (2D) cell cultures, and in most cases have used only a matched pair of mutant/wild-type (WT) cell lines. To improve the probability of finding translatable targets, it might be beneficial to use more physiologically relevant cellular models and to screen larger panels of cell lines (Cox et al., 2014). In an effort to discover translatable mutant KRAS synthetic lethal targets, we have performed a 3D clonogenic synthetic lethal screen with a diverse small-molecule library of 280,000 compounds across six mutant KRAS-dependent cell lines and four KRAS-independent cell lines. We report here the results from this screen, and the identification and characterization of dihydroorotate dehydrogenase (DHODH) as the target of one of the most KRAS mutant-selective compounds. As expected, DHODH inhibition prevents de novo pyrimidine biosynthesis, which appears to be a particularly important pathway in the growth/survival of KRAS mutant cells. DHODH inhibition also substantially decreases cellular levels of glutamine and glutamate, suggesting a connection to the previously established glutamine dependence of KRAS mutant cells (Son et al., 2013, Weinberg et al., 2010). We also show that brequinar, a DHODH inhibitor that has previously failed to demonstrate efficacy in clinical trials as an anticancer agent (Moore et al., 1993), exhibits strong in vivo antitumor activity in a KRAS mutant pancreatic tumor xenograft model. The links observed in vitro between KRAS status and a requirement for metabolic flux through the de novo pyrimidine biosynthetic pathway suggest new strategies for the clinical application of potent DHODH inhibitors against KRAS mutant cancers.