Formation | 2015 |
---|---|
Type | Scientific society |
Legal status | 501(c)(3) nonprofit organization |
Purpose | Increasing the quality and reproducibility of biomedical research using chemical probes. |
Headquarters | Sutton, London |
Location | |
Board of Governors | Milka Kostic, Jonathan Baell, Alessio Ciulli, Jeremy L. Jenkins, Akane Kawamura, Yung Lie, Laetitia Martin, Osamu Nakanishi, Jonathan, S. Rosenblum, Jason Sheltzer |
Key people | Paul Workman, Aled Edwards, Bissan Al-Lazikani, Ian Collins, Susanne Müller-Knapp, Albert A. Antolin, Domenico Sanfelice, Alisa Crisp |
Website | www |
The Chemical Probes Portal is an open, online resource whose purpose is to identify and make available high quality chemical probes for use in biological research and drug discovery. While chemical probes can be valuable tools to elucidate signal transduction pathways and to validate new drug targets, many of the probes that are in use are not selective and therefore can give very misleading results. [1]
The Portal recommends chemical probes based on ratings provided by its Scientific Advisory Board (SAB), a group of experts in the fields of chemical biology, medicinal chemistry, and pharmacology, who (1) determine which are the best chemical probes available and (2) establish guidelines for using them.
After years of publishing best practice guidelines for the selection and use of chemical probes, [2] [3] [4] [5] many in the field agreed that publications were insufficient to disseminate this type of information. In July 2015, these experts, led by the Structural Genomics Consortium (SGC), collaborated to publish an overview of the misuse of chemical probes and the impact that misuse has on the reliability of research. [6] A prototype website was launched by the SGC in conjunction with the publication.
This publication and the portal were launched at the same time the biomedical research community was becoming aware of problems in the reproducibility of much of the scientific literature. According to an economic impact study, $28 billion per year is spent on irreproducible biomedical research in the US alone. The most common reasons that studies prove irreproducible include problems with the selection of reagents and reference materials (36%), study design (28%), data analysis and reporting (25%), and laboratory protocols (11%). [7] Errors in the selection and application of chemical probes can contribute to waste in each of these categories. Given the context and the need, the prototype portal was largely well received by the scientific community, [8] [9] [10] [11] [12] although it was noted that the prototype portal was launched with a very small number (seven to be exact) of probes. [13]
In 2016, the SGC recruited staff to take over the portal, establish it as an independent organization, and build it into a reputable source for information about chemical probes. This new organization was supported with funds provided by the Wellcome Trust and the SGC. By the end of the first quarter, the portal’s new leadership incorporated the organization in North Carolina, US, established a board of directors and developed a plan to grow the portal through a community-driven, expert-curation process. The portal was re-launched on June 30, 2016 with this operations plan integrated into the site, more data about the existing probes (~100) in the portal, recommendations for the use of those probes.
The Portal works closely with Target 2035, a global effort to provide high quality chemical or biological probes for every protein in the human proteome by 2035.
In June 2016, the Portal announced its founding Board of Directors [14] including Mark Bunnage (Vertex), Aled Edwards (SGC), Yung Lie (Damon Runyon Cancer Research Foundation), Herbert Waldmann (Max Planck Institute of Molecular Physiology), Tim Willson (SGC UNC), and Paul Workman (ICR).
The SAB, [15] an international collection of experts from the fields of medicinal chemistry, pharmacology, and chemical biology, was created to provide the Portal with expert advice. The SAB considers submitted chemical probes and makes recommendations for their use. In addition to considering chemical probes, SAB members also provide strategic and scientific advice to portal staff to help ensure the portal stays in tune with the scientific community and its needs. The Portal issued an open call for new SAB members to join the effort in May 2016, which will remain open until the SAB reaches its target membership.
The Portal opted for an expert peer-review process [16] to vet and rate chemical probes. Key to this process is the Portal’s SAB, who represent a global community and multiple professional environments (e.g., pharma, biotech, clinical centers or academia). These experts bring diverse experiences and expertise to the Portal to help it provide balanced advice to scientists who want to use chemical probes in their experiments without becoming chemical probe experts themselves.
The Portal’s review process involves three main steps: 1) probe submission, 2) triage, 3) review and publication. In the first step, scientists who have generated and published chemical probes can submit their probes for consideration. Initially, the portal can only accept submissions for probes that have been published.
Portal staff consider completed probe submissions to determine whether they are eligible for review. Submissions must meet three criteria to merit consideration by the SAB: 1) the probe is published, 2) it has been deposited into a public database such as PubChem (the Portal can now deposit submitted probes to PubChem on behalf of its users), and 3) there are data supporting its validation in a cellular and/or in vivo model system. Probes that do not meet these criteria are not sent to the SAB for review but are retained in the database. Probes that meet all three criteria are reviewed.
SAB members review each probe submission, including the publication reporting the probe, and rate the probe for its use in cellular and/or in vivo model systems (e.g., mice). Probes are evaluated for use in these two types of systems independently, meaning that it is not necessary for a probe to be validated for use in model organisms for it to be considered and endorsed by the portal. The portal has not strictly defined criteria that translate into Portal endorsement. Rather, the Portal relies on its experts, their experience with and knowledge of specific protein targets to assess the quality of a probe. SAB members can comment on each probe, providing guidance to users to ensure they understand the strengths and weaknesses of a probe before they use it.
Probes are published on the Portal along with a highlight of the probe’s validation data, and it takes a few weeks for the SAB ratings (denoted with 0 to 4 stars) to emerge. Probe pages also contain SAB comments and links to related databases or sources (e.g., journals) where additional information can be found. Probes must receive an average of 3 stars to earn an endorsement from the Portal.
In chemistry, a reagent or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms reactant and reagent are often used interchangeably, but reactant specifies a substance consumed in the course of a chemical reaction. Solvents, though involved in the reaction mechanism, are usually not called reactants. Similarly, catalysts are not consumed by the reaction, so they are not reactants. In biochemistry, especially in connection with enzyme-catalyzed reactions, the reactants are commonly called substrates.
Products are the species formed from chemical reactions. During a chemical reaction, reactants are transformed into products after passing through a high energy transition state. This process results in the consumption of the reactants. It can be a spontaneous reaction or mediated by catalysts which lower the energy of the transition state, and by solvents which provide the chemical environment necessary for the reaction to take place. When represented in chemical equations, products are by convention drawn on the right-hand side, even in the case of reversible reactions. The properties of products such as their energies help determine several characteristics of a chemical reaction, such as whether the reaction is exergonic or endergonic. Additionally, the properties of a product can make it easier to extract and purify following a chemical reaction, especially if the product has a different state of matter than the reactants.
In chemical biology, bioorthogonal chemical reporter is a non-native chemical functionality that is introduced into the naturally occurring biomolecules of a living system, generally through metabolic or protein engineering. These functional groups are subsequently utilized for tagging and visualizing biomolecules. Jennifer Prescher and Carolyn R. Bertozzi, the developers of bioorthogonal chemistry, defined bioorthogonal chemical reporters as "non-native, non-perturbing chemical handles that can be modified in living systems through highly selective reactions with exogenously delivered probes." It has been used to enrich proteins and to conduct proteomic analysis.
Stuart L. Schreiber is a scientist at Harvard University and co-Founder of the Broad Institute. He has been active in chemical biology, especially the use of small molecules as probes of biology and medicine. Small molecules are the molecules of life most associated with dynamic information flow; these work in concert with the macromolecules that are the basis for inherited information flow.
Aled Morgan Edwards is the founder and Chief Executive of the Structural Genomics Consortium, a charitable public-private partnership. He is Professor of Medical Genetics and Medical Biophysics at the University of Toronto, Visiting Professor of Chemical Biology at the University of Oxford, and Adjunct Professor at McGill University.
The Structural Genomics Consortium (SGC) is a public-private-partnership focusing on elucidating the functions and disease relevance of all proteins encoded by the human genome, with an emphasis on those that are relatively understudied. The SGC places all its research output into the public domain without restriction and does not file for patents and continues to promote open science. Two recent publications revisit the case for open science. Founded in 2003, and modelled after the Single Nucleotide Polymorphism Database (dbSNP) Consortium, the SGC is a charitable company whose Members comprise organizations that contribute over $5,4M Euros to the SGC over a five-year period. The Board has one representative from each Member and an independent Chair, who serves one 5-year term. The current Chair is Anke Müller-Fahrnow (Germany), and previous Chairs have been Michael Morgan (U.K.), Wayne Hendrickson (U.S.A.), Markus Gruetter (Switzerland) and Tetsuyuki Maruyama (Japan). The founding and current CEO is Aled Edwards (Canada). The founding Members of the SGC Company were the Canadian Institutes of Health Research, Genome Canada, the Ontario Research Fund, GlaxoSmithKline and Wellcome Trust. The current Members comprise Bayer Pharma AG, Bristol Myers Squibb, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, Pfizer, and Takeda.
In the field of chemical biology, a chemical probe is a small molecule that is used to study and manipulate a biological system such as a cell or an organism by reversibly binding to and altering the function of a biological target within that system. Probes ideally have a high affinity and binding selectivity for one protein target as well as high efficacy. By changing the phenotype of the cell, a molecular probe can be used to determine the function of the protein with which it interacts.
LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used for experiments aiming to target PI3K uniquely.
Open-notebook science is the practice of making the entire primary record of a research project publicly available online as it is recorded. This involves placing the personal, or laboratory, notebook of the researcher online along with all raw and processed data, and any associated material, as this material is generated. The approach may be summed up by the slogan 'no insider information'. It is the logical extreme of transparent approaches to research and explicitly includes the making available of failed, less significant, and otherwise unpublished experiments; so called 'dark data'. The practice of open notebook science, although not the norm in the academic community, has gained significant recent attention in the research and general media as part of a general trend towards more open approaches in research practice and publishing. Open notebook science can therefore be described as part of a wider open science movement that includes the advocacy and adoption of open access publication, open data, crowdsourcing data, and citizen science. It is inspired in part by the success of open-source software and draws on many of its ideas.
Michelle C. Y. Chang is a Professor of Chemistry and Chemical and Biomolecular Engineering at the University of California, Berkeley, and is a recipient of several young scientist awards for her research in biosynthesis of biofuels and pharmaceuticals.
Derek Lowe is a medicinal chemist working on preclinical drug discovery in the pharmaceutical industry. Lowe has published a blog about this field, "In the Pipeline", since 2002 and is a columnist for the Royal Society of Chemistry's Chemistry World.
Linda Carol Hsieh-Wilson is an American chemist and the Milton and Rosalind Chang Professor of Chemistry at the California Institute of Technology. She is known for her work in chemical neurobiology on understanding the structure and function of carbohydrates in the nervous system. Her studies have revealed critical roles for carbohydrates and protein glycosylation in fundamental processes ranging from cellular metabolism to memory storage. She is a member of the American Academy of Arts and Sciences and was elected to the National Academy of Sciences in 2022.
Chemical genetics is the investigation of the function of proteins and signal transduction pathways in cells by the screening of chemical libraries of small molecules. Chemical genetics is analogous to classical genetic screen where random mutations are introduced in organisms, the phenotype of these mutants is observed, and finally the specific gene mutation (genotype) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds. Phenotypic screening of chemical libraries is used to identify drug targets or to validate those targets in experimental models of disease. Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments. Chemical genetics can serve as a unifying study between chemistry and biology. The approach was first proposed by Tim Mitchison in 1994 in an opinion piece in the journal Chemistry & Biology entitled "Towards a pharmacological genetics".
Gideon John Davies is a Professor of Chemistry in the Structural Biology Laboratory (YSBL) at the University of York, UK. Davies is best known for his ground-breaking studies into carbohydrate-active enzymes, notably analysing the conformational and mechanistic basis for catalysis and applying this for societal benefit. In 2016 Davies was apppointed the Royal Society Ken Murray Research Professor at the University of York.
BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.
Polypharmacology is the design or use of pharmaceutical agents that act on multiple targets or disease pathways.
Nicholas John Turner, is a British chemist and a Professor in the Department of Chemistry at The University of Manchester. His research in general is based on biochemistry and organic chemistry, specifically on biotechnology, cell biology, biocatalysis and organic synthesis.
Jonathan Baell is an Australian medicinal chemist. He is a research professor in medicinal chemistry at the Monash Institute of Pharmaceutical Sciences (MIPS), the Director of the Australian Translational Medicinal Chemistry Facility and a Chief Investigator at the ARC Centre for Fragment-Based Design. He is also the President of the International Chemical Biology Society. His research focuses on the early stages of drug discovery, including high-throughput screening (HTS) library design, hit-to-lead and lead optimization for the treatment of a variety of diseases, such as malaria and neglected diseases.
Alessio Ciulli is an Italian British biochemist. Currently, he is the Professor of Chemical & Structural Biology at the School of Life Sciences, University of Dundee, when he founded and directs Dundee' new Centre for Targeted Protein Degradation (CeTPD). He is also the scientific co-founder and advisor of Amphista Therapeutics.
Target 2035 is a global effort or movement to discover open science, pharmacological modulator(s) for every protein in the human proteome by the year 2035. The effort is led by the Structural Genomics Consortium with the intention that this movement evolves organically. Target 2035 has been borne out of the success that chemical probes have had in elevating or de-prioritizing the therapeutic potential of protein targets. The availability of open access pharmacological tools is a largely unmet aspect of drug discovery especially for the dark proteome.