Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen ...accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.
The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes ...that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
Both the efficiency and the stereoselectivity in baker's‐yeast‐mediated reduction of ketones are strongly influenced by both the presence and the position of sulfur substituents, or indeed by the use ...of sulfur‐containing additives. Interestingly the oxidation level of the sulfur substituent has a powerful impact on the outcome of the yeast reduction. It is apparent that use of the sulfone moiety as a substituent to influence the efficiency and stereoselectivity in ketone reduction is substantially more effective than use of the analogous sulfide and sulfoxide moieties.
Stereochemical control in the baker's yeast reduction of ketones through the introduction of sulfur functional groups (sulfides, sulfoxides and sulfones) or sulfur‐containing additives has attracted considerable attention. This microreview provides a summary of developments to date, highlighting the synthetic utility of the yeast‐mediated ketone reduction influenced by the presence of sulfur moieties.
Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium–BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to ...β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.
The baker's yeast mediated reduction of 2-acetyl-3-methyl sulfolane 1 to provide the corresponding alcohol 2 is described. Excellent efficiency and enantioselectivity (>98% ee) has been achieved ...under these mild environmentally benign reaction conditions. In direct contrast, the chemical reduction of 1 proceeds with poor yield (=<25%) and diastereocontrol.
The novel preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via the cyclization of (2-aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in the presence of phosphorus ...oxychloride is described. This methodology is demonstrated for a range of urea substrates with aminoimidazole products obtained in good yields and with excellent levels of purity.
An efficient synthetic approach leading to introduction of the hydroxymethyl group to an aryl moiety via combination of the Bouveault formylation and hydride reduction has been optimized using a ...rational, mechanistic-based approach. This approach enabled telescoping of the two steps into a single efficient process, readily amenable to scaleup.
Absolute stereochemistry of oils and viscous liquids can be difficult to determine. Co-crystallization involves generating a crystalline material consisting of more than one neutral compound. The ...combination of co-crystallization with both X-ray diffraction and chiral HPLC was particularly powerful in overcoming these difficulties for a series of chiral 3-arylbutanoic acids. Co-crystallization offers advantages over salt formation because co-crystals dissociate in solution, meaning identical HPLC conditions can be used for both the materials of interest and their co-crystals.
There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing ...researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.
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