Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules.

Discovery of 2,4-1-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.

Herein we report the discovery of 2,4-1-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1-dicarboxamide scaffold, showing remarkable kinome selectivity.

Short sleep duration as a risk factor for hypercholesterolemia: analyses of the National Longitudinal Study of Adolescent Health.

Study Objectives: To explore the relationship between sleep duration in adolescence and hypercholesterolemia in young adulthood. Experimental sleep restriction has been shown to significantly increase total cholesterol and LDL cholesterol levels in women. Short sleep duration has been found in cross sectional studies to be associated with higher total cholesterol and lower HDL cholesterol levels.

Insomnia and sleep duration as mediators of the relationship between depression and hypertension incidence.

Background: Depression has been found to predict the incidence of hypertension and other adverse cardiovascular events in prospective studies. Insomnia and short sleep duration, which are typical symptoms of depression, have also been shown to increase the risk for hypertension incidence. Insomnia is associated with increased activation of the hypothalamic-pituitary-adrenal axis, and short sleep duration raises average 24-h blood pressure, which over time could lead to structural adaptations that gradually reset the entire cardiovascular system to operate at an elevated pressure equilibrium.