Background: Biological activities of nontoxic A␤42 peptides remain unclear in Alzheimer disease. Results: A␤ species are taken up in the nucleus of cells by a nonregulated mechanism, but only A␤42 plays a role in gene transcription. Conclusion: A␤42 may act as a transcriptional regulator, similar to the cytoplasmic fragment AICD. Significance: Genes regulated by nuclear A␤42 could represent alternative targets for therapeutic approaches.

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

Highlights d A screen for inhibitory compounds of colorectal cancer spheroids identifies NCT02 d NCT02 acts as a molecular glue and induces degradation of CCNK and CDK12 d Knockout of CCNK or CDK12 and targeted CCNK degradation decrease tumor growth d TP53 deficiency and consensus molecular subtype 4 predict sensitivity to NCT02

The availability of a chemical probe to study the role of a specific domain of a protein in a concentration- and time-dependent manner is of high value. Herein, we report the identification of a highly potent and selective ERK5 inhibitor BAY-885 by high-throughput screening and subsequent structure-based optimization. ERK5 is a key integrator of cellular signal transduction, and it has been shown to play a role in various cellular processes such as proliferation, differentiation, apoptosis, and cell survival. We could demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, which is in contrast to the results obtained by RNAi technology.