Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity.

6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations.

On-campus student employment as a form of leadership development.

Student employment is a common co-curricular activity among undergraduate students. Previous studies have primarily focused on the impact of employment on academic outcomes and post-graduation labor market success. Although there is an assumption that on-campus student employment influences leadership learning, there is a lack of research directly exploring this topic. Therefore, this study explores how on-campus student employment influences leadership capacity development in undergraduate students who worked in a department in Student Affairs. Findings suggest that on-campus student employment influenced leadership capacity development in undergraduate students.

Exploring the Motivation to Lead in a Demanding Environment: The Role of Achievement Values, Grit, and Psychological Capital.

As leaders across organizational contexts continue to face volatile and often stressful environments, a greater understanding of the psychological underpinnings of the motivation to lead (MTL) in challenging circumstances is needed. Based on a sample of 242 cadets holding leadership positions in a military college, we utilized a distal and proximal conceptualization of MTL to test achievement values, grit, and psychological capital (PsyCap) as antecedents to the three factors of MTL. Controlling for gender, prior leadership positions, and leader tenure, regression modeling revealed grit and achievement values to be positively associated with affective/identity MTL, while PsyCap was positively associated with all three MTL factors. In addition, PsyCap mediated the relation between grit and all three MTL factors. Our findings suggest that PsyCap plays a critical proximal role in MTL in demanding environments, and further implications for research and practice are discussed.

BI 5700, a Selective Chemical Inhibitor of IκB Kinase 2, Specifically Suppresses Epithelial-Mesenchymal Transition and Metastasis in Mouse Models of Tumor Progression.

Increasing evidence suggests that processes termed epithelial-mesenchymal transitions (EMTs) play a key role in therapeutic resistance, tumor recurrence, and metastatic progression. NF-κB signaling has been previously identified as an important pathway in the regulation of EMT in a mouse model of tumor progression. However, it remains unclear whether there is a broad requirement for this pathway to govern EMT and what the relative contribution of IKK family members acting as upstream NF-κB activators is toward promoting EMT and metastasis. To address this question, we have used a novel, small-molecule inhibitor of IκB kinase 2 (IKK2/IKKß), termed BI 5700. We investigated the role of IKK2 in a number of mouse models of EMT, including TGFß-induced EMT in the mammary epithelial cell line EpRas, CT26 colon carcinoma cells, and 4T1 mammary carcinoma cells. The latter model was also used to evaluate in vivo activities of BI 5700.We found that BI 5700 inhibits IKK2 with an IC(50) of 9 nM and was highly selective as compared to other IKK family members (IKK1, IKKε, and TBK1) and other kinases. BI 5700 effectively blocks NF-κB activity in EpRas cells and prevents TGFß-induced EMT. In addition, BI 5700 reverts EMT in mesenchymal CT26 cells and prevents EMT in the 4T1 model. Oral application of BI 5700 significantly interferes with metastasis after mammary fat-pad injection of 4T1 cells, yielding fewer, smaller, and more differentiated metastases as compared to vehicle-treated control animals. We conclude that IKK2 is a key regulator of both the induction and maintenance of EMT in a panel of mouse tumor progression models and that the IKK2 inhibitor BI 5700 constitutes a promising candidate for the treatment of metastatic cancers.

Alpha-methyltryptamine sulfonamide derivatives as novel glucocorticoid receptor ligands.

Alpha-methyltryptamine sulfonamides were identified as human glucocorticoid receptor (hGR) ligands in an ultra high throughput screening (UHTS) campaign. Described will be the hit-to-lead activities, including parallel and single point analog synthesis to map the scaffold. Ligands were identified that exhibited 30 nM binding to hGR. The SAR and selectivity of these compounds will be discussed.