Optimization of the Lead Compound NVP BHG712 as Colorectal Cancer Inhibitor

The ephrin type A receptor 2 EPHA2 kinase belongs to the largest family of receptor tyrosine kinases. There are several indications of an involvement of EPHA2 in the development of infectious diseases and cancer. Despite pharmacological potential, EPHA2 is an under examined target protein. In this study, we synthesized a series of derivatives of the inhibitor NVP BHG712 and triazine based compounds. These compounds were evaluated to determine their potential as kinase inhibitors of EPHA2, including elucidation of their binding mode X ray crystallography , affinity microscale thermophoresis , and selectivity Kinobeads assay . Eight inhibitors showed affinities in the low nanomolar regime K D lt;10 nM . Testing in up to seven colon cancer cell lines that express EPHA2 reveals that several derivatives feature promising effects for the control of human colon carcinoma. Thus, we have developed a set of powerful tool compounds for fundamental new research on the interplay of EPH receptors in a cellular contex

Designing low-carbon power systems for Great Britain in 2050 that are robust to the spatiotemporal and inter-annual variability of weather

The design of cost-effective power systems with high shares of variable renewable energy (VRE) technologies requires a modelling approach that simultaneously represents the whole energy system combined with the spatiotemporal and inter-annual variability of VRE. Here, we soft-link a long-term energy system model, which explores new energy system configurations from years to decades, with a high spatial and temporal resolution po wer system model that captures VRE variability from hours to years. Applying this methodology to Great Britain for 2050, we find that VRE-focused power system design is highly sensitive to the inter-annual variability of weather and that planning based on a single year can lead to operational inadequacy and failure to meet long-term decarbonization objectives. However, some insights do emerge that are relatively stable to weather-year. Reinforcement of the transmission system consistently leads to a decrease in system costs while electricity storage and flexible generation, needed to integrate VRE into the system, are generally deployed close to demand centres