The impact of unemployment on the transition to parenthood

This paper seeks to advance our understanding about the impact of unemployment on fertility. From a theoretical perspective, both negative and positive effects might be expected. Existing empirical studies have produced contradictory results, partly because of varying institutional contexts, the use of different measures, and left-censoring problems. We address these theoretical and methodological problems in the extant literature. Our data comes from the German Life History Study (GLHS) and, in particular, the data on the 1971 cohort, which was collected in two representative and retrospective surveys conducted in East and West Germany in 1996-1998 and 2005. Using monthly information, we perform event history analysis to identify the timing of fertility for both men and women conditional on a number of covariates. We present our results as a comparison between East and West Germany, as the institutional contexts, the labour markets, and the value systems differ considerably between the two parts of the German state

The Substrate-Activity-Screening methodology applied to receptor tyrosine kinases: A proof-of-concept study.

Protein kinases are widely recognized as important therapeutic targets due to their involvement in signal transduction pathways. These pathways are tightly controlled and regulated, notably by the ability of kinases to selectively phosphorylate a defined set of substrates. A wide variety of disorders can arise as a consequence of abnormal kinase-mediated phosphorylation and numerous kinase inhibitors have earned their place as key components of the modern pharmacopeia. Although “traditional” kinase inhibitors typically act by preventing the interaction between the kinase and ATP, thus stopping substrate phosphorylation, an alternative approach consists in disrupting the protein-protein interaction between the kinase and its downstream partners. We herein report a proof-of-concept application of the Substrate Activity Screening methodology to Insulin-like Growth Factor 1 Receptor as a tool for the discovery of substrate-site-directed tyrosine kinase inhibitors

Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors

Protein phosphorylation by kinases is of critical importance for the regulation of many cellular functions. When kinases are deregulated numerous biological processes are affected, which may cause a variety of diseases. Therefore, kinase inhibition plays an important role for therapeutic intervention. A number of kinase inhibitors have been approved as drugs, initially in oncology where promiscuous (multi-kinase) inhibitors were most efficacious. Exploring kinase inhibitor selectivity and promiscuity for therapy is among the most challenging aspects of kinase drug discovery. Herein, we thoroughly analyze a kinase profiling experiment in which 637 designated inhibitors of p38α MAP kinase (p38α) were tested against a panel of 60 kinases distributed across the human kinome. In this experiment, only 19% of the inhibitors were found to be promiscuous when the median p38α inhibition level was applied as an activity threshold. Promiscuous inhibitors had a median value of two targets per compound, and many of these inhibitors were only active against the p38α and closely related JNK3 enzymes. Promiscuity cliffs were identified and analyzed in a network representation revealing structural modifications that were implicated in triggering compound promiscuity. Taken together, the findings revealed a high degree of selectivity of designated p38α directed inhibitors although they target the ATP binding site that is largely conserved across the human kinome

Substrate profiling of IGF-1R and InsR: Identification of a potent pentamer substrate.

Protein kinases are widely recognized as important therapeutic targets due to their involvement in signal transduction pathways. These pathways are tightly controlled and regulated, notably by the ability of kinases to selectively phosphorylate a defined set of substrates. As part of a study on the substrate requirements of Insulin-like Growth Factor 1 Receptor (IGF-1R) and Insulin Receptor (InsR), we evaluated and applied a universal assay system able to monitor the phosphorylation of unlabelled peptides of any length in real time. In contrast to already reported profiling methodologies, we were able to assess the kcat/KM ratio of peptides as short as tetramers. Notably, we were able to identify an efficient pentamer substrate that exhibited kinetic properties close to those of a 250-amino acid protein derived from IRS-1, a natural substrate of IGF-1R and InsR

Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of Huntington’s Disease

Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinases 3 and p38α (mitogen-activated protein) MAP kinase. A library of 39 derivatives was prepared and evaluated in a kinase activity test for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α inhibitors being 6g (IC50 JNK3: 18 nM, p38α: 30 nM) and 14d (IC50 JNK3: 26 nM, p38α: 34 nM). They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington’s disease

Identification and optimisation of a 4',5-bisthiazole series of selective phosphatidylinositol-3 kinase alpha inhibitors

Abstract: Exploring the affinity-pocket binding moiety of a 2-aminothiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors using a parallel-synthesis approach led to the identification of a novel 4',5-bisthiazole sub-series. The synthesis and optimisation of both the affinity pocket and (S)-proline amide moieties within this 4',5-bisthiazole sub-series are described. From this work a number of analogues, including 14 (A66) and 24, were identified as potent and selective PI3Kα inhibitor in vitro tool compounds

Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region

A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members

Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.

The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPPIV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral phamacokinetic profile in the rat

Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor

Most kinase inhibitors discovered to date block the ATP binding site which is highly conserved among different kinases and, as a result, such compounds very often suffer from lack of kinase selectivity. Discovery of inhibitors targeting novel allosteric kinase sites is still considered very challenging. In our previous report we described discovery of allosteric inhibitors, such as 1, targeting PAK1 kinase. Herein we report our structure-based optimization strategy yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was co-crystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase