An inhibitor of oxidative phosphorylation exploits cancer vulnerability.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Application of samarium diiodide-mediated cyclizations for the construction of polycyclic compounds. I. A general route toward the synthesis of the cladiellin skeleton and synthesis of the 3,7-diastereomer of polyanthellin A. II. Construction of bicyclic ring systems via a transannular cyclization strategy

Cladiellin diterpenes are a family of marine metabolites isolated from gorgonians and soft corals. Since the isolation of the first member of this family in 1968, more than sixty cladiellin natural products have been reported. Cladiellin diterpenes display a wide array of biological activity. In addition, they possess a unique structure: a rare oxabicyclic ring system that is composed of a hexahydroisobenzofuran moiety and an oxacyclononane unit. They contain at least six stereogenic centers. An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed in this laboratory. The approach is based on a Sml2-mediated cyclization reaction for the construction of the oxacyclononane unit. A [4+3] annulation strategy was used to create the octahydroisobenzofuran moiety. This route provides the cladiellin skeleton in only fourteen steps without the use of protecting groups. The present approach also enabled the synthesis of the 3,7-diastereomer of the natural product polyanthellin A. The development of efficient methods for the construction of polycyclic compounds has been a longstanding objective of synthetic organic chemists. Traditionally, bicyclic ring systems are created via two approaches: (1) annulation of a sidechain onto an existing ring and (2) cycloaddition reactions. In addition to these strategies, a third possible approach is to form bicycles via transannular transformations. However, this strategy has not been systematically examined. Our research group has initiated a project that focuses on investigating the synthetic utility of the transannular ring formation strategy. To test the viability of this approach, the ketyl-olefin coupling, a method previously developed in this laboratory, was examined. During the course of this research, the transannular cyclization of cyclooctene, cyclodecene and cycloundecene derivatives was investigated. It was concluded that the transannular ketyl-olefin coupling proceeds with high yield, diastereoselectivity, and in the case larger ring-sized compounds, with excellent regioselectivity. These results demonstrate that the transannular cyclization strategy provides efficient access to bicyclic ring systems

Application of samarium diiodide-mediated cyclizations for the construction of polycyclic compounds. I. A general route toward the synthesis of the cladiellin skeleton and synthesis of the 3,7-diastereomer of polyanthellin A. II. Construction of bicyclic ring systems via a transannular cyclization strategy

Cladiellin diterpenes are a family of marine metabolites isolated from gorgonians and soft corals. Since the isolation of the first member of this family in 1968, more than sixty cladiellin natural products have been reported. Cladiellin diterpenes display a wide array of biological activity. In addition, they possess a unique structure: a rare oxabicyclic ring system that is composed of a hexahydroisobenzofuran moiety and an oxacyclononane unit. They contain at least six stereogenic centers. An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed in this laboratory. The approach is based on a Sml2-mediated cyclization reaction for the construction of the oxacyclononane unit. A [4+3] annulation strategy was used to create the octahydroisobenzofuran moiety. This route provides the cladiellin skeleton in only fourteen steps without the use of protecting groups. The present approach also enabled the synthesis of the 3,7-diastereomer of the natural product polyanthellin A. The development of efficient methods for the construction of polycyclic compounds has been a longstanding objective of synthetic organic chemists. Traditionally, bicyclic ring systems are created via two approaches: (1) annulation of a sidechain onto an existing ring and (2) cycloaddition reactions. In addition to these strategies, a third possible approach is to form bicycles via transannular transformations. However, this strategy has not been systematically examined. Our research group has initiated a project that focuses on investigating the synthetic utility of the transannular ring formation strategy. To test the viability of this approach, the ketyl-olefin coupling, a method previously developed in this laboratory, was examined. During the course of this research, the transannular cyclization of cyclooctene, cyclodecene and cycloundecene derivatives was investigated. It was concluded that the transannular ketyl-olefin coupling proceeds with high yield, diastereoselectivity, and in the case larger ring-sized compounds, with excellent regioselectivity. These results demonstrate that the transannular cyclization strategy provides efficient access to bicyclic ring systems

Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation

Summary: The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations. : Loss-of-function genetics screen reveals a synthetically lethal interaction between OXPHOS inhibition and phosphogluconate dehydrogenase (PGD) inactivation. Sun et al. provide an example of targeting tumor metabolism in a genetically predefined context to maximize therapeutic impact and propose PGD as a therapeutic target for fumarate hydratase-deficient HLRCC. Keywords: synthetic lethality, PGD, OXPHOS, tumor metabolism, metabolic vulnerability, fumarate hydratase, redox homeostasis, functional genomics, hereditary leiomyomatosis renal cell carcinoma, pentose phosphate pathwa