Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect

Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts

Metaheuristics for Transmission Network Expansion Planning

This chapter presents the characteristics of the metaheuristic algorithms used to solve the transmission network expansion planning (TNEP) problem. The algorithms used to handle single or multiple objectives are discussed on the basis of selected literature contributions. Besides the main objective given by the costs of the transmission system infrastructure, various other objectives are taken into account, representing generation, demand, reliability and environmental aspects. In the single-objective case, many metaheuristics have been proposed, in general without making strong comparisons with other solution methods and without providing superior results with respect to classical mathematical programming. In the multi-objective case, there is a better convenience of using metaheuristics able to handle conflicting objectives, in particular with a Pareto front-based approach. In all cases, improvements are still expected in the definition of benchmark functions, benchmark networks and robust comparison criteria

Range expansion of the invasive brown marmorated stinkbug, <em>Halyomorpha halys</em>: an increasing threat to field, fruit and vegetable crops worldwide

International audienceThe brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), has emerged as a harmful invasive insect pest in North America and Europe in the 1990s and 2000s, respectively. Native to eastern Asia, this highly polyphagous pest (> 120 different host plants) is spreading rapidly worldwide, notably through human activities. The increasing global importance of the pest suggests that more coordinated actions are needed to slow its spread and mitigate negative effects in invaded areas. Prevention of large-scale outbreaks will require accurate identification and effective mitigation tools to be rapidly developed and widely implemented. In this short review, we update the current distribution of H. halys, discuss potential geographic range expansion based on passive and active dispersal and provide insight on the economic, environmental and social impact associated with H. halys