Crowdsourced mapping of unexplored target space of kinase inhibitors

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome. The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts

Relating underrepresented genomic DNA patterns and tiRNAs: the rule behind the observation and beyond

Abstract Background One of the central problems of post-genomic biology is the understanding of regulatory network of genes. Traditionally the problem is approached from the protein-DNA interaction perspective. In recent years various types of noncoding RNAs appeared on the scene as new potent players of the game. The exact role of these molecules in gene expression control is mostly unknown at present, while their importance is generally recognized. Results The Human and Mouse genomes have been screened with a statistical model for sequence patterns underrepresented in these genomes, and a subset of motifs, named spanions, has been identified. The common portion of the motif lists of the two species is 75% indicating evolutionary conservation of this feature. These motifs are arranged in clusters at close proximity of distinct genetic landmarks: 5' ends of genes, exon side of the exon/intron junctions and 5' ends of 3' UTRs. The length of the clusters is typically in the 20 to 25 bases range. The findings are in agreement with the known C/G bias of promoter regions while access much more sequential information than the simple composition based model. In the Human genome the recently reported transcription initiation RNAs (tiRNAs) are typically transcribed from these spanion clusters according to the presented results. The spanion clusters account for 70% of the published tiRNAs. Apparently, the model access the common statistical feature of this new and mostly uncharacterized non-coding RNA class and, in this way, supports the experimental observations with theoretical background. Conclusions The presented results seem to support the emerging model of the RNA-driven eukaryotic gene expression control. Beyond that, the model detects spanion clusters at genetic positions where no tiRNA counterpart was considered and reported. The GO-term analysis of genes with high concentration of spanion clusters in their promoter proximal region indicates involvement in gene regulatory processes. The results of the analysis suggest that the gene regulatory potential of the small non-coding RNAs is grossly underestimated at present. Reviewers This article was reviewed by Frank Eisenhaber, Sandor Pongor and Rotem Sorek (nominated by Doron Lancet).</p

Measuring Nonapoptotic Caspase Activity with a Transgenic Reporter in Mice

International audienceThe protease caspase-3 is a key mediator of apoptotic programmed cell death. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no simple method for mapping and quantifying nonapoptotic caspase activity (NACA) in rodent brains. We therefore generated a transgenic mouse expressing a highly sensitive and specific fluorescent reporter of caspase activity, with peak signal localized to the nucleus. As a proof of concept, we first obtained evidence that NACA influences neurophysiology in an amygdalar circuit. Then focusing on the amygdala, we were able to quantify a sex-specific persistent elevation in caspase activity in females after restraint stress. This simple in vivo caspase activity reporter will facilitate systems-level studies of apoptotic and nonapoptotic phenomena in behavioral and pathologic models