The Ontario Institute for Cancer Research (OICR) is a not-for-profit organization based in Toronto, Ontario, Canada that focuses on the prevention, early detection, diagnosis and treatment of cancer. OICR intends to make Ontario more effective in knowledge transfer and commercialization while maximizing the health and economic benefits of research findings for the people of Ontario. OICR was launched in 2005 by the Government of Ontario, which provides funding through the Ministry of Colleges and Universities. The Institute employs more than 300 people at its research hub at the MaRS Centre in downtown Toronto and funds more than 1,900 scientific staff at hospital-based research institutes and universities around the province. In 2018 is was the highest funder of cancer research in Canada.
Chromanes are privileged scaffolds in medicinal chemistry because they exhibit diverse biological activities. Their stereoselective synthesis has become a critical objective in drug development. The emergence of organocatalysis has sparked a paradigm shift in synthetic chemistry by offering a highly selective alternative to traditional metal-catalyzed reactions. This review discusses the transformative impact of organocatalyzed reactions on the asymmetric synthesis of chromane derivatives, focusing on key classes of catalysts such as chiral phosphoric acid, chiral amines, bifunctional systems, and others reported since 2020. Organocatalysis not only achieves high levels of stereocontrol but also adheres to the principles of green chemistry by eliminating toxic metals and enabling mild reaction conditions. These advancements diversify synthetic methodologies and establish organocatalysis as a fundamental approach in the sustainable synthesis of bioactive chromanes.
The Reactome Knowledgebase (https://reactome.org) is a freely accessible, expert-curated, open-source, and open-data resource that describes human biology in molecular detail. It spans normal physiology as well as disease mechanisms, including the impact of genetic variation and drug action. Reactome content is continuously expanded and revised, with automated workflows now monitoring retracted publications to maintain data integrity. To meet the needs of a growing user base, Reactome has launched a redesigned Angular-based interface with enhanced accessibility, modular architecture, and a hierarchy of visualization tools: ReacFoam for global pathway overviews, enhanced high-level diagrams for intuitive navigation, and redesigned entity level views (ELVs) enriched with chemical structures, animated protein models, and a new "compare mode" to contrast normal and disease states. New analysis tools support multi-omics integration and customizable visualizations. Recent innovations include the React-to-me chatbot for natural language interaction, community-driven tutorials, and an open Figma icon library. Reactome's sustainability and compliance with FAIR data principles were recently recognized with CoreTrustSeal certification and its designation as a Global Core Biodata and ELIXIR resource, reinforcing its role as a trusted global knowledgebase.
The third Critical Assessment of Computational Hit-finding Experiments (CACHE) challenged computational teams to identify chemically novel ligands targeting the macrodomain 1 of SARS-CoV-2 Nsp3, a promising coronavirus drug target. Twenty-three groups deployed diverse design strategies to collectively select 1739 ligand candidates. While over 85% of the designed molecules were chemically novel, the best experimentally confirmed hits were structurally similar to previously published compounds. Confirming a trend observed in CACHE #1 and #2, two of the best-performing workflows used compounds selected by physics-based computational screening methods to train machine learning models able to rapidly screen large chemical libraries, while four others used exclusively physics-based approaches. Three pharmacophore searches and one fragment growing strategy were also part of the seven winning workflows. While active molecules discovered by CACHE #3 participants largely mimicked the adenine ring of the endogenous substrate, ADP-ribose, preserving the canonical chemotype commonly observed in previously reported Nsp3-Mac1 ligands, they still provide novel structure-activity relationship insights that may inform the development of future antivirals. Collectively, these results show that multiple molecular design strategies can efficiently converge on similar potent molecules.
G protein-coupled receptor (GPCR) signaling is regulated by four ubiquitously expressed GPCR kinase isoforms (GRKs), namely GRK2, GRK3, GRK5, and GRK6. Overexpression of individual GRKs occurs in diseases like cancer and heart failure, prompting a search for potent GRK inhibitors. While various in silico and in vitro approaches exist, few methods assess inhibitor efficacy in cellular systems. To address this, we used HEK293 cell lines co-expressing the β2 adrenergic receptor (β2) and one GRK isoform on a quadruple GRK2/3/5/6 knockout background (ΔQ-GRK). We evaluated the inhibition of isoproterenol (ISO)-induced T360/S364-β2 phosphorylation using the 7TM phosphorylation assay. This combination allowed comprehensive evaluation of commercially available GRK inhibitors. We conclude that compound 8h (GRK2/3 inhibitor) and compound 18 (GRK5/6 inhibitor) are highly recommendable tools for the study of GPCR phosphorylation and function in cellular systems. Together, these cell-based GRK inhibitor assays can facilitate medium- to high-throughput screening of future GRK-targeted drug candidates. A GRK-isoform immunoassay was used to quantify GPCR phosphorylation and evaluate the potency of GRK inhibitors in a controlled cellular system.
B-cell lymphoma 6 (BCL6) is a transcriptional repressor protein central to the development and maintenance of germinal centers (GCs) during the humoral immune response. BCL6 is often deregulated in diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin's lymphoma, and inhibition of the protein-protein interaction between BCL6 and corepressors has been implicated as a therapeutic strategy. Based on a previously identified small molecule binding site on the BCL6 BTB domain, we carried out a virtual screen and identified a set of high micromolar screening hits. One series was advanced to a low micromolar confirmed hit via iterative rounds of compound optimization guided by structure activity relationships and co-crystal structures. Overall, we were able to use a rational, structure-based drug design approach to identify and advance a novel series of pyrrolopyrimidinone BCL6 BTB inhibitors.
