ABSTRACT
canSAR (https://cansar.ai) is the largest public cancer drug discovery and translational research knowledgebase. Now hosted in its new home at MD Anderson Cancer Center, canSAR integrates billions of experimental measurements from across molecular profiling, pharmacology, chemistry, structural and systems biology. Moreover, canSAR applies a unique suite of machine learning algorithms designed to inform drug discovery. Here, we describe the latest updates to the knowledgebase, including a focus on significant novel data. These include canSAR's ligandability assessment of AlphaFold; mapping of fragment-based screening data; and new chemical bioactivity data for novel targets. We also describe enhancements to the data and interface.
Subject(s)
Antineoplastic Agents , Drug Discovery , Knowledge Bases , Translational Research, Biomedical , Humans , Algorithms , Neoplasms/drug therapy , Neoplasms/geneticsABSTRACT
canSAR (http://cansar.icr.ac.uk) is the largest, public, freely available, integrative translational research and drug discovery knowledgebase for oncology. canSAR integrates vast multidisciplinary data from across genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and more. It also provides unique data, curation and annotation and crucially, AI-informed target assessment for drug discovery. canSAR is widely used internationally by academia and industry. Here we describe significant developments and enhancements to the data, web interface and infrastructure of canSAR in the form of the new implementation of the system: canSARblack. We demonstrate new functionality in aiding translation hypothesis generation and experimental design, and show how canSAR can be adapted and utilised outside oncology.
Subject(s)
Computational Biology/methods , Databases, Genetic , Drug Discovery/methods , Knowledge Bases , Neoplasms/genetics , Translational Research, Biomedical/methods , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Data Mining/methods , Genomics/methods , Humans , Internet , Medical Oncology/methods , Molecular Structure , Neoplasms/metabolism , Proteomics/methods , User-Computer InterfaceABSTRACT
Chemical probes are essential tools for understanding biological systems and for target validation, yet selecting probes for biomedical research is rarely based on objective assessment of all potential compounds. Here, we describe the Probe Miner: Chemical Probes Objective Assessment resource, capitalizing on the plethora of public medicinal chemistry data to empower quantitative, objective, data-driven evaluation of chemical probes. We assess >1.8 million compounds for their suitability as chemical tools against 2,220 human targets and dissect the biases and limitations encountered. Probe Miner represents a valuable resource to aid the identification of potential chemical probes, particularly when used alongside expert curation.
Subject(s)
Molecular Probes/chemistry , Small Molecule Libraries/chemistry , Chemistry, Pharmaceutical , HumansABSTRACT
PURPOSE: The high attrition rate of cancer drug development programs is a barrier to realizing the promise of precision oncology. We have examined whether the genetic insights from genome-wide association studies of cancer can guide drug development and repurposing in oncology. MATERIALS AND METHODS: Across 37 cancers, we identified 955 genetic risk variants from the National Human Genome Research Institute-European Bioinformatics Institute genome-wide association study catalog. We linked these variants to target genes using strategies that were based on linkage disequilibrium, DNA three-dimensional structure, and integration of predicted gene function and expression. With the use of the Informa Pharmaprojects database, we identified genes that are targets of unique drugs and assessed the level of enrichment that would be afforded by incorporation of genetic information in preclinical and phase II studies. For targets not under development, we implemented machine learning approaches to assess druggability. RESULTS: For all preclinical targets incorporating genetic information, a 2.00-fold enrichment of a drug being successfully approved could be achieved (95% CI, 1.14- to 3.48-fold; P = .02). For phase II targets, a 2.75-fold enrichment could be achieved (95% CI, 1.42- to 5.35-fold; P < .001). Application of genetic information suggests potential repurposing of 15 approved nononcology drugs. CONCLUSION: The findings illustrate the value of using insights from the genetics of inherited cancer susceptibility discovery projects as part of a data-driven strategy to inform drug discovery. Support for cancer germline genetic information for prospective targets is available online from the Institute of Cancer Research.
Subject(s)
Drug Development/methods , Genetic Predisposition to Disease/genetics , Neoplasms/drug therapy , Neoplasms/genetics , HumansABSTRACT
canSAR (http://cansar.icr.ac.uk) is a publicly available, multidisciplinary, cancer-focused knowledgebase developed to support cancer translational research and drug discovery. canSAR integrates genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and druggability data. canSAR is widely used to rapidly access information and help interpret experimental data in a translational and drug discovery context. Here we describe major enhancements to canSAR including new data, improved search and browsing capabilities, new disease and cancer cell line summaries and new and enhanced batch analysis tools.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Knowledge Bases , Neoplasms/metabolism , Animals , Cell Line, Tumor , Clinical Trials as Topic , Gene Expression , Humans , Neoplasm Proteins/chemistry , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms/geneticsABSTRACT
canSAR (http://cansar.icr.ac.uk) is a public integrative cancer-focused knowledgebase for the support of cancer translational research and drug discovery. Through the integration of biological, pharmacological, chemical, structural biology and protein network data, it provides a single information portal to answer complex multidisciplinary questions including--among many others--what is known about a protein, in which cancers is it expressed or mutated, and what chemical tools and cell line models can be used to experimentally probe its activity? What is known about a drug, its cellular sensitivity profile and what proteins is it known to bind that may explain unusual bioactivity? Here we describe major enhancements to canSAR including new data, improved search and browsing capabilities and new target, cancer cell line, protein family and 3D structure summaries and tools.
Subject(s)
Antineoplastic Agents/chemistry , Databases, Genetic , Drug Discovery , Neoplasms/genetics , Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Internet , Knowledge Bases , Mutation , Protein Conformation , Protein Interaction Mapping , Proteins/classification , Proteins/genetics , Proteins/metabolism , Translational Research, BiomedicalABSTRACT
Selecting the best targets is a key challenge for drug discovery, and achieving this effectively, efficiently and systematically is particularly important for prioritizing candidates from the sizeable lists of potential therapeutic targets that are now emerging from large-scale multi-omics initiatives, such as those in oncology. Here, we describe an objective, systematic, multifaceted computational assessment of biological and chemical space that can be applied to any human gene set to prioritize targets for therapeutic exploration. We use this approach to evaluate an exemplar set of 479 cancer-associated genes, reveal the tension between biological relevance and chemical tractability, and describe major gaps in available knowledge that could be addressed to aid objective decision-making. We also propose drug repurposing opportunities and identify potentially druggable cancer-associated proteins that have been poorly explored with regard to the discovery of small-molecule modulators, despite their biological relevance.
