Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway

The characteristic of deformability and quantitative description of the microstructure of hot-deformed Ni-Fe superalloy

The paper presents the results of research concerning the influence of hot plastic working parameters on the deformability and microstructure of a Ni-Fe superalloy. The research was performed on a torsion plastometer in the range of temperatures of 900-1150°C, at a strain rates 0.1 and 1.0 s-1. Plastic properties of the alloy were characterized by the worked out flow curves and the temperature relationships of flow stress and strain limit. The structural inspections were performed on microsections taken from plastometric samples after so-called “freezing”. The stereological parameters as the recrystallized grain size, inhomogenity and grain shape have been determined. Functional relations between the Zener-Hollomon parameter and the maximum yield stress and the average grain area have been developed and the activation energy for hot working has been estimated

The Microstructure and Mechanical Properties of Cylindrical Elements from Steel 38Mn6 after Continuous Induction Heating

The paper deals with the influence of induction surface hardening on the microstructure and mechanical properties of cylindrical elements made of steel 38Mn6. The first stage was based on computer simulation of the induction hardening process. The second stage - experiments were provided on laboratory stand for induction surface hardening located at the Silesian University of Technology. Microstructure tests were conducted on light and scanning microscopes. The hardness penetration pattern and thickness of hardened layer were marked. It was found that due to properly chosen parameters of the process, the appropriate properties and thickness of hardened layer were achieved

The Microstructure and Mechanical Properties of Cylindrical Elements from Steel 38Mn6 after Continuous Induction Heating

The paper deals with the influence of induction surface hardening on the microstructure and mechanical properties of cylindrical elements made of steel 38Mn6. The first stage was based on computer simulation of the induction hardening process. The second stage - experiments were provided on laboratory stand for induction surface hardening located at the Silesian University of Technology. Microstructure tests were conducted on light and scanning microscopes. The hardness penetration pattern and thickness of hardened layer were marked. It was found that due to properly chosen parameters of the process, the appropriate properties and thickness of hardened layer were achieved

Bueroalltag unter der Lupe Schwachstellen von Arbeitsbedingungen erkennen und beheben - ein Praxisleitfaden

Available from TIB Hannover: T95B1297+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman