Design of a dual ERK5 kinase activation and autophosphorylation inhibitor to block cancer stem cell activity.

The importance of ERK5 kinase signaling in tumorigenicity, metastasis, and drug resistance of cancer stem cells (CSCs) has been recognized recently, and we report a unique dual inhibitor that blocks binding of the ERK5 activator and ERK5 autophosphorylation simultaneously. The conventional ATP-binding site inhibitors have not yet yielded expected level of anti-cancer effects, due to complexities in converting ERK5 activation into CSC biological effects. We designed the first ERK5-targeted anti-CSC dual active hetero-bivalent inhibitor that blocks the regulatory peptide interaction involved in ERK5 kinase activation and that simultaneously inhibits the conventional ATP-binding pocket as well. We utilized two assay systems to independently prove disruption of these two ERK5 activities via a single compound. We also showed that this compound inhibited CSC activities, such as colony formation, cell proliferation, and migration.

Ecophysiological Features of Polar Soil Unicellular Microalgae1.

Due to their ecological, physiological, and molecular adaptations to low and varying temperatures, as well as varying seasonal irradiances, polar non-marine eukaryotic microalgae could be suitable for low-temperature biotechnology. Adaptations include the synthesis of compounds from different metabolic pathways that protect them against stress. Production of biological compounds and various biotechnological applications, for instance, water treatment technology, are of interest to humans. To select prospective strains for future low-temperature biotechnology in polar regions, temperature and irradiance of growth requirements (Q10 and Ea of 10 polar soil unicellular strains) were evaluated. In terms of temperature, three groups of strains were recognized: (i) cold-preferring where temperature optima ranged between 10.1 and 18.4°C, growth rate 0.252 and 0.344 · d-1 , (ii) cold- and warm-tolerating with optima above 10°C and growth rate 0.162-0.341 · d-1 , and (iii) warm-preferring temperatures above 20°C and growth rate 0.249-0.357 · d-1 . Their light requirements were low. Mean values Q10 for specific growth rate ranged from 0.7 to 3.1. The lowest Ea values were observed on cold-preferring and the highest in the warm-preferring strains. One strain from each temperature group was selected for PN and RD measurements. The PN :RD ratio of the warm-preferring strains was less affected by temperature similarly as Q10 and Ea. For future biotechnological applications, the strains with broad temperature tolerance (i.e., the group of cold- and warm-tolerating and warm-preferring strains) will be most useful.