The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies

A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

Background: Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers. Methods: Male and non-pregnant female aged 18-50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study. Results: Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4-8 and 4-12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141-188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4-6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed. Conclusions: The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/201

Influence of different atmospheres on molten salt chemistry and its effect on steel corrosion

Dispatchability of renewable solar energy can be realized by integrating thermal energy storage units. In concentrating solar power plants the use of sensible heat storage based on molten nitrate salts, typically Solar Salt (Na,K//NO3), has proven most beneficial in the last decade. However, a crucial parameter that affects the long-term performance of the TES unit however, is the sustainability and reliability which is directly linked to the material performance of the molten salt and the construction material. Metallic corrosion is one of the biggest concerns due to the harsh conditions provided by the redox active molten nitrate salts. The mechanisms of corrosion are thought to be well understood which is reflected by a significant number of publications in the last decades. Despite, an essential parameter is often ignored or underestimated in many studies: the molten salt chemistry. This work is one of the first addressing directed degradation of Solar Salt by controlling the gas atmosphere in the storage system, thus driving the formation of corrosive impurities, especially oxide species. Austenitic, stainless Cr,Ni-steel and ferritic Cr-steel samples are subjected to the different operating conditions to demonstrate the variations in corrosivity as a function of gas atmosphere and additionally of artificially added chloride impurities. The experimental matrix allows for a comprehensive analysis of the influence of different corrosive species on the stability of different steel types over the course of 1.200h experiments performed at 560°C

How molten nitrate salt altering affects steel corrosion

Thermal Energy Storage (TES) coupled with concentrating solar power (CSP) has proven competitive with conventional solar harvesting techniques such as PV but offers substantial advantages due to the sheer presence of the TES unit itself. Modern CSP-TES plants accommodate 2-tank based storage units which operate between 290°C and 565°C using molten nitrate salts, such as the classical Solar Salt, a 60-40 wt.-% NaNO3-KNO3 mixture. Despite their expected life-time of 20+ years and the availability of numerous corrosion studies being published to date, a critical and comprehensive view on both the molten salt (MS) chemistry and the corrosion effects is often not presented and it remains unclear how these phenomena are associated. The results of a series of experiments conducted recently by DLR and MPA outline that the MS chemistry has drastic effects on corrosion rates, and additionally that the type of impurity drives the corrosion mechanism. This impact will be presented using a martensitic high temperature steel (T91) and an austenitic stainless steel (AISI 316Ti) exposed to isothermal storage for 1.200 h at 560 °C in Solar Salt with precise control of the atmosphere, either synthetic air or nitrogen, to gain chemically equilibrated or continuously decomposing MS. Moreover, the same set of experiments has been carried out with the addition of impurities using 0.5 wt. % chlorides. As a short outlook it can be stated that AISI 316Ti and T91 show different susceptibility to impurities, as well as differential dependence on atmospheres. While the corrosion behavior of AISI 316Ti was influenced by the nitrite- and oxide-ion ratio in the MS, T91 was more sensitive to the presence of chloride impurities forming thicker oxide layers with the tendency to spall. The work demonstrates that the gas environment and thus the MS chemistry, investigated by chromatography, titration and atomic absorption spectroscopy, directly affect the corrosion behavior. It can be concluded that a simultaneous examination of MS chemistry and metallic corrosion is indispensable to understand metallic corrosion phenomena in molten nitrate salts

Projektabschlussbericht zum "Teilvorhaben Korrosionsverhalten" (FKZ 0325497B (MPA) + FKZ 0325497A (DLR)) des Verbundvorhabens "MS-Store - Flüssigsalzspeicher-Testanlage und neue Fluide"

Ziel des Teilvorhabens „Korrosionsverhalten“ im Verbundprojekt MS-Store - Flüssigsalzspeicher-Testanlage und neue Fluide war es, Anforderungen an die zu verwendenden Werkstoffe, die durch hohe Temperaturen bei Energiespeichern in solarthermischen Kraftwerken auftreten, hinsichtlich des Korrosionsverhaltens zu untersuchen, um die Lebensdauer solcher Kraftwerke zu erhöhen, sowie substantielle wissenschaftliche Ergebnisse in diesem Anwendungsgebiet zu erhalten. Mittels Auslagerungsversuchen bei 560°C wurden die Abtragsraten für verschiedene Stähle in unterschiedlichen Nitratsalzmischungen in Abhängigkeit von der Auslagerungsdauer isotherm und zyklisch bestimmt. Im Anschluss wurden mittels diverser elektronenmikroskopischer und röntgenografischer Untersuchungsmethoden (FIB, REM, EDX; TEM; XRD) die Oxidschichtentwicklung und -beschaffenheit, die Phasenzusammensetzung der Oxidschicht, die Gefügestruktur des Grundwerkstoffs, sowie der erfolgte korrosive Angriff analysiert. Mittels elektrochemischer Prüfmethoden (OCP, IE, EIS) wurde das Korrosionsverhalten der Stähle in-situ bei Temperaturen zwischen 410 und 560°C und in Abhängigkeit der Reinheit der Salzschmelze analysiert, sowie die Stabilität der Oxidschichten evaluiert. Es zeigte sich eine eindeutige Überlegenheit der Korrosionsbeständigkeit der untersuchten Cr,Ni-Stähle gegenüber des hochwarmfesten Cr-Stahls, speziell in Salzschmelzen die Chloridgehalte ab 0,5 Gew.-% aufweisen. Weiterhin ließ sich eine eindeutige Abhängigkeit des Korrosionsverhaltens von der gewählten Temperatur nachweisen; die Beständigkeit ist bei 410°C deutlich höher, als bei 560°C. Die mehrlagigen Oxidschichten bestehen aus Cr,Fe-Mischoxiden, sowie reinen Cr-/Fe-Oxiden. Sie weisen eine hohe Porosität, sowie eine schlechte Haftung auf dem Grundmaterial auf. Nach langer Auslagerung entstehen zusätzlich Na,Fe-reiche Oxide. Im Grundmaterial bildeten sich durch Stickstoffeintrag aus der Salzschmelze an den Korngrenzen oder auch im kompletten Gefüge Gefügeveränderungen, in Form von Cr-Nitriden. Neuartige elektrochemische Untersuchungen in Nitratsalzschmelzen bei hohen Temperaturen wurden mittels elektrochemischer Impedanzspektroskopie (EIS) durchgeführt. Dabei wurde die Abhängigkeit des Korrosionsverhaltens von Temperatur, Salzreinheit und Beschaffenheit und Stabilität der Oxidschichten ermittelt. EIS eignet sich sehr gut, um schnell fundierte Aussagen über ein vorliegendes Korrosionssystem zu treffen und kann auch in anderen Schmelzen, sowie anderen Werkstoffen oder Parametern eingesetzt werden. Die quantitative Auswertung dieser Messmethode ist sehr komplex und benötigt anwendungsbasierte Weiterentwicklung. Dennoch konnte das Auftreten des Breakaway-Effektes mittels dieser Methodik bestätigt werden. Außerdem wurde die Tendenz von Chrom zur Lösung in der Salzschmelze festgestellt, sowie Änderungen im Nitrat/Nitrit-Verhältnis, bedingt durch Zersetzungsreaktionen der Salzschmelze beobachtet. Diese Effekte können zu veränderten Eigenschaften der Schmelze hinsichtlich ihrer Wärmespeicherkapazität, ihrer generellen Stabilität und ihrer Korrosivität führen. Die im Verlauf des Teilvorhabens gewonnenen Erkenntnisse erweitern den bisher in der Fachliteratur präsentierten Kenntnisstand des Korrosionsverhaltens von anwendungsrelevanten Stählen in Nitratsalzschmelzen deutlich. Sie ermöglichen eine gezielte Materialauswahl für Planer und Konstrukteure von solarthermischen Kraftwerken

Impact of Solar Salt aging on corrosion of martensitic and austenitic steel for concentrating solar power plants

This work addresses the influence of molten nitrate salt chemistry on the corrosion behavior of a martensitic high temperature steel and an austenitic stainless steel. It is one of the first addressing controlled degradation of Solar Salt by controlling the gas atmosphere on top of the melt, thus driving the formation of corrosive ions, mainly oxide ions but also nitrite ions. The stainless steel and high temperature steel samples are subjected to the different operating conditions to demonstrate the variations in corrosivity as a function of gas atmosphere and additionally of artificially added chloride impurities. The results indicate that the atmosphere has a direct impact on the formation of corrosive oxide and nitrite ions. The low Cr-steel is found to be more sensitive to chloride impurities, while the stainless steel corrosion is enhanced by the presence of nitrites and oxide ions. All studies are supported by profound molten salt analysis throughout the experiments including the analysis of nitrate, nitrite, oxide and chromate ions as well as cation compositions. Steel samples are analyzed by scanning electron microscopy methods and corrosion rates are extrapolated from 1200 h experiments