In shade‐intolerant plants such as Arabidopsis, a reduction in the red/far‐red (R/FR) ratio, indicative of competition from other plants, triggers a suite of responses known as the shade avoidance ...syndrome (SAS). The phytochrome photoreceptors measure the R/FR ratio and control the SAS. The phytochrome‐interacting factors 4 and 5 (PIF4 and PIF5) are stabilized in the shade and are required for a full SAS, whereas the related bHLH factor HFR1 (long hypocotyl in FR light) is transcriptionally induced by shade and inhibits this response. Here we show that HFR1 interacts with PIF4 and PIF5 and limits their capacity to induce the expression of shade marker genes and to promote elongation growth. HFR1 directly inhibits these PIFs by forming non‐DNA‐binding heterodimers with PIF4 and PIF5. Our data indicate that PIF4 and PIF5 promote SAS by directly binding to G‐boxes present in the promoter of shade marker genes, but their action is limited later in the shade when HFR1 accumulates and forms non‐DNA‐binding heterodimers. This negative feedback loop is important to limit the response of plants to shade.
Hit finding, scaffold hopping, and structure-activity relationship studies are important tasks in rational drug discovery. Implementation of these tasks strongly depends on the availability of ...compounds similar to a known bioactive molecule. SwissSimilarity is a web tool for low-to-high-throughput virtual screening of multiple chemical libraries to find molecules similar to a compound of interest. According to the similarity principle, the output list of molecules generated by SwissSimilarity is expected to be enriched in compounds that are likely to share common protein targets with the query molecule and that can, therefore, be acquired and tested experimentally in priority. Compound libraries available for screening using SwissSimilarity include approved drugs, clinical candidates, known bioactive molecules, commercially available and synthetically accessible compounds. The first version of SwissSimilarity launched in 2015 made use of various 2D and 3D molecular descriptors, including path-based FP2 fingerprints and ElectroShape vectors. However, during the last few years, new fingerprinting methods for molecular description have been developed or have become popular. Here we would like to announce the launch of the new version of the SwissSimilarity web tool, which features additional 2D and 3D methods for estimation of molecular similarity: extended-connectivity, MinHash, 2D pharmacophore, extended reduced graph, and extended 3D fingerprints. Moreover, it is now possible to screen for molecular structures having the same scaffold as the query compound. Additionally, all compound libraries available for screening in SwissSimilarity have been updated, and several new ones have been added to the list. Finally, the interface of the website has been comprehensively rebuilt to provide a better user experience. The new version of SwissSimilarity is freely available starting from December 2021.
Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains ...unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.
Abstract
At several stages of drug discovery, bioisosteric replacement is a common and efficient practice to find new bioactive chemotypes or to optimize series of molecules toward drug candidates. ...The critical steps consisting in selecting which molecular moiety should be replaced by which other chemical fragment is often relying on the expertise of specialists. Nowadays, valuable support can be obtained through the wealth of dedicated structural and knowledge data. The present article details the update of SwissBioisostere, a database of >25 millions of unique molecular replacements with data on bioactivity, physicochemistry, chemical and biological contexts extracted from the literature and related resources. The content of the database together with analysis and visualization capacities is freely available at www.swissbioisostere.ch.
Estimating protein targets of compounds based on the similarity principle-similar molecules are likely to show comparable bioactivity-is a long-standing strategy in drug research. Having previously ...quantified this principle, we present here a large-scale evaluation of its predictive power for inferring macromolecular targets by reverse screening an unprecedented vast external test set of more than 300,000 active small molecules against another bioactivity set of more than 500,000 compounds. We show that machine-learning can predict the correct targets, with the highest probability among 2069 proteins, for more than 51% of the external molecules. The strong enrichment thus obtained demonstrates its usefulness in supporting phenotypic screens, polypharmacology, or repurposing. Moreover, we quantified the impact of the bioactivity knowledge available for proteins in terms of number and diversity of actives. Finally, we advise that developers of such approaches follow an application-oriented benchmarking strategy and use large, high-quality, non-overlapping datasets as provided here.
The SwissBioisostere database (http://www.swissbioisostere.ch) contains information on molecular replacements and their performance in biochemical assays. It is meant to provide researchers in drug ...discovery projects with ideas for bioisosteric modifications of their current lead molecule, as well as to give interested scientists access to the details on particular molecular replacements. As of August 2012, the database contains 21,293,355 datapoints corresponding to 5,586,462 unique replacements that have been measured in 35,039 assays against 1948 molecular targets representing 30 target classes. The accessible data were created through detection of matched molecular pairs and mining bioactivity data in the ChEMBL database. The SwissBioisostere database is hosted by the Swiss Institute of Bioinformatics and available via a web-based interface.
Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer ...therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
The identification of patient-specific tumor antigens is complicated by the low frequency of T cells specific for each tumor antigen. Here we describe NeoScreen, a method that enables the sensitive ...identification of rare tumor (neo)antigens and of cognate T cell receptors (TCRs) expressed by tumor-infiltrating lymphocytes. T cells transduced with tumor antigen-specific TCRs identified by NeoScreen mediate regression of established tumors in patient-derived xenograft mice.
The front cover picture shows how a computer can predict gastrointestinal absorption and brain access for small molecules. The pills illustrate the main objects of the method, namely therapeutically ...relevant compounds in the context of drug design, discovery, and development. The chemical structures falling from the open pill evoke the capacity to run the calculation on chemical libraries. The pleasant atmosphere and common laptop suggest the will to hide technical complexity and to foster the ease of usage and interpretation. To this end, we developed the Brain Or IntestinaL EstimateD permeation method (or BOILED‐Egg) through highly parallelized Monte Carlo simulations. The model proposes an accurate and intuitive classification of small molecules based on lipophilicity and polarity. Simultaneous predictions for both brain and intestinal permeation are obtained from two physicochemical descriptors and efficiently translated into molecular design thanks to the speed, statistical robustness, conceptual simplicity, and clear graphical output. The BOILED‐Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of medicinal chemistry projects, to the evaluation of drug candidates for development. More information can be found in the Communication by Antoine Daina and Vincent Zoete on page 1117 in Issue 11, 2016 (DOI: 10.1002/cmdc.201600182).
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