Substrate Activity Screening with Kinases: Discovery of Small‐Molecule Substrate‐Competitive c‐Src Inhibitors

Substrate‐competitive kinase inhibitors represent a promising class of kinase inhibitors, however, there is no methodology to selectively identify this type of inhibitor. Substrate activity screening was applied to tyrosine kinases. By using this methodology, the first small‐molecule substrates for any protein kinase were discovered, as well as the first substrate‐competitive inhibitors of c‐Src with activity in both biochemical and cellular assays. Characterization of the lead inhibitor demonstrates that substrate‐competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP‐competitive inhibitors. SASsy inhibitors : Small‐molecule substrate‐competitive inhibitors of the tyrosine kinase c‐Src were discovered through the application of substrate activity screening (SAS). Characterization of the lead inhibitor demonstrates that substrate‐competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP‐competitive inhibitors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107499/1/7010_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107499/2/anie_201311096_sm_miscellaneous_information.pd

Optimisation de forme multi-critère d'une structure non-linéaire complexe

Airless tyres are complex structures working in multi-physic contexts. The geometry and the combination of materials must be wisely chosen to manufacture competitive designs. Multiple innovations were proposed at different scales, from the micro-scale concerning the grip of the tread and the thermal response in the contact zone with the ground to the meter-scale concerning the global architecture of the airless tyre, with structural, vibratory challenges. At the latter macro-scale, designers particularly focus on the elastic response of the structure to correctly guide a vehicle towards its trajectory. Different tools based on several optimization methods exist to assist manufacturers reaching the optimal geometry responding to the best comprise of performances. In our special case, we develop the geometric shape optimization in an elastic mechanical context. We propose a gradient method to minimize optimization criteria. Yet multiple aspects lead the optimization complex, such as non linearities. We develop the complexity linked to the contact condition between the airless tyre and the ground. The contact condi- tion involves non linearities in the mechanical problem. The contact is treated by Nitsche’s method, which is a consistent method and does not need the use of Lagrangian multipli- ers. Therefore we study geometric shape optimization with contact through a Nitsche-based formulation in elasticity. The contact condition also introduces a non differentiability in the usual sense through the optimization problem. A weaker notion of differentiability is introduced to ensure the formulation of shape derivatives of the optimization criteria. In addition, the airless tyre is largely solicited and high deformations might occur, involving other non linearities in the mechanical problem. Thereby the shape optimization procedure is first presented in linear elasticity where the mathematical framework offers the possibility to analyze the shape sensitivity and ensure shape derivatives for the criteria for the gradient descent method. Then the shape optimization is extended to large deformations for more realistic applications.Les pneumatiques sans air sont des structures complexes dont le comportement fait intervenir différentes physiques. Afin de proposer une conception performante, la géométrie d'un pneumatique sans air et les matériaux qui composent une telle structure font l'objet de choix de recherche rigoureux. Différents outils de conception existent afin d'obtenir le meilleur compromis de performances, et en particulier, nous nous intéressons dans cette thèse à des stratégies d'optimisation de forme dans un contexte d'élasticité avec une condition de contact entre le pneumatique sans air et le sol. Nous montrons en particulier l'avantage de traiter efficacement cette condition, notamment par la méthode de Nitsche, méthode consistante et pour laquelle, nous proposons une analyse de convergence dans le cadre d'élasticité linéaire. Enfin, comme le pneumatique sans air est largement sollicité en grandes déformations, la méthodologie d'optimisation de forme est étendue dans le cas de modèles d'élasticité non linéaires afin de traiter des applications plus réalistes

Optimisation de forme multi-critère d'une structure non-linéaire complexe

Les pneumatiques sans air sont des structures complexes dont le comportement fait intervenir différentes physiques. Afin de proposer une conception performante, la géométrie d'un pneumatique sans air et les matériaux qui composent une telle structure font l'objet de choix de recherche rigoureux. Différents outils de conception existent afin d'obtenir le meilleur compromis de performances, et en particulier, nous nous intéressons dans cette thèse à des stratégies d'optimisation de forme dans un contexte d'élasticité avec une condition de contact entre le pneumatique sans air et le sol. Nous montrons en particulier l'avantage de traiter efficacement cette condition, notamment par la méthode de Nitsche, méthode consistante et pour laquelle, nous proposons une analyse de convergence dans le cadre d'élasticité linéaire. Enfin, comme le pneumatique sans air est largement sollicité en grandes déformations, la méthodologie d'optimisation de forme est étendue dans le cas de modèles d'élasticité non linéaires afin de traiter des applications plus réalistes.Airless tyres are complex structures working in multi-physic contexts. The geometry and the combination of materials must be wisely chosen to manufacture competitive designs. Multiple innovations were proposed at different scales, from the micro-scale concerning the grip of the tread and the thermal response in the contact zone with the ground to the meter-scale concerning the global architecture of the airless tyre, with structural, vibratory challenges. At the latter macro-scale, designers particularly focus on the elastic response of the structure to correctly guide a vehicle towards its trajectory. Different tools based on several optimization methods exist to assist manufacturers reaching the optimal geometry responding to the best comprise of performances. In our special case, we develop the geometric shape optimization in an elastic mechanical context. We propose a gradient method to minimize optimization criteria. Yet multiple aspects lead the optimization complex, such as non linearities. We develop the complexity linked to the contact condition between the airless tyre and the ground. The contact condi- tion involves non linearities in the mechanical problem. The contact is treated by Nitsche’s method, which is a consistent method and does not need the use of Lagrangian multipli- ers. Therefore we study geometric shape optimization with contact through a Nitsche-based formulation in elasticity. The contact condition also introduces a non differentiability in the usual sense through the optimization problem. A weaker notion of differentiability is introduced to ensure the formulation of shape derivatives of the optimization criteria. In addition, the airless tyre is largely solicited and high deformations might occur, involving other non linearities in the mechanical problem. Thereby the shape optimization procedure is first presented in linear elasticity where the mathematical framework offers the possibility to analyze the shape sensitivity and ensure shape derivatives for the criteria for the gradient descent method. Then the shape optimization is extended to large deformations for more realistic applications

Optimisation de forme géométrique multi-critère et multi-chargement d'une structure non linéaire complexe : le pneumatique sans air.

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Diastereoselective synthesis of alpha -tocopherol : a new concept for the formation of chromanols

A diastereoselective synthesis of alpha-tocopherol (93% de) was achieved via two key steps, (i) a highly diastereoselective Shi epoxidn. of trisubstituted alkene I and (ii) an acid supported, "anti-Baldwin" epoxide ring opening under inversion of configuration leading to the 6-membered chromanol ring

Biomimetic chromanol cyclisation : a common route to to α-Tocotrienol and α-Tocopherol

A common synthetic route to alpha-tocotrienol and alpha-tocopherol has been accomplished by a biomimetic cyclization that yields the chromanol ring.  The chirality at C2 of the chromanol was induced by a covalently attached chiral dipeptide.  Its terminal Asp participates in the enantioface-selective protonation of the double bond of the alpha-tocotrienol precursor I.  alpha-Tocotrienol was diastereoselectively hydrogenated to alpha-tocopherol

Shape optimization of a linearly elastic rolling structure under unilateral contact using Nitsche's method and cut finite elements

The main motivation of this work is to develop a numerical strategy for the shape optimization of a rolling elastic structure under contact with respect to a uniform rolling criterion. A first objective is to highlight the influence on the treatment of the contact terms. To do so, we present a numerical comparison between a penalty-based approach and the use of Nitsche's method which is known to have good consistency properties. A second task concerns the construction of an objective functional to force the uniform rolling criterion. Here, we present and compare two different strategies that will lead to quite similar results. All the numerical experiments proposed in this paper were performed using a fictitious domain approach coupled with a level set representation of the shape and the use of a cut finite element method to approximate the elastic equation