Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration.

Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affinity Sirt2 selective Sirtuin-Rearranging Ligands (SirReals) that inhibit both Sirt2-dependent deacetylation and defatty-acylation in vitro and in cells. We show that simultaneous inhibition of both Sirt2 activities results in strongly reduced levels of the oncoprotein c-Myc and an inhibition of cancer cell migration. Furthermore, we describe the development of a NanoBRET-based assay for Sirt2, thereby providing a method to study cellular target engagement for Sirt2 in a straightforward and accurately quantifiable manner. Applying this assay, we could confirm cellular Sirt2 binding of our new Sirt2 inhibitors and correlate their anticancer effects with their cellular target engagement.

Enhancements in biologically effective ultraviolet radiation following volcanic eruptions.

Aerosols injected into the stratosphere by large volcanic eruptions may induce ozone destruction through processes including heterogeneous chemical reactions. The effect of ozone reductions on surface ultraviolet irradiation is not obvious, however, because aerosols also increase the reflection of sunlight. Here we use a radiative transfer model to estimate the changes in biologically effective ultraviolet radiation (UV-BE) at the Earth's surface produced by the El Chichón (1982) and Mount Pinatubo (1991) eruptions. We find that in both cases surface UV-BE intensity can increase because the effect of ozone depletion outweighs the increased scattering.