European Lead Factory Research Articles

The European lead factory—an experiment in collaborative drug discovery

The European Lead Factory (ELF) is a unique collaborative public–private partnership aiming to deliver innovative drug discovery starting points and improving the value generated by ultra-High Throughput Screening (uHTS) approaches. Composed of a unique compound collection derived from private pharmaceutical company collections and complemented with new chemistries from a unique public collection, it offers a unique uHTS platform accessible to both private companies and publicly funded researchers. One of the key challenges in setting up ELF has been to balance access to screening results with protecting the value of compounds in the collection. Through an ‘honest data broker’ data management platform and a royalty reward scheme based on achieved milestones, ELF has been able to overcome these challenges. Set up in 2013, it has already accepted 42 targets for screening, submitted by publicly funded researchers, and generated 12 Qualified Hit Lists. In addition, 55,000 new library compounds have been generated by the public partners and added to the 320,000 compounds made available by the companies. Although it faced many challenges in becoming operational, this unique experiment in collaboration is already generating exciting results that will hopefully, eventually lead to better medicines and tools to advance our biological knowledge, and should act as a template for future approaches in the area.

Erratum: European Lead Factory hits its stride

Nature Reviews Drug Discovery 15, 221–222 (2016) In the version of the article originally published, Merck & Co. was incorrectly listed as one of the pharmaceutical partners of the European Lead Factory, instead of Merck KGaA. This error has been corrected in the online versions of the article.

Design and Synthesis of Fsp(3)-Rich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening.

The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented.

Erratum: European Lead Factory hits its stride

Nature Reviews Drug Discovery 15, 221–222 (2016) In the version of this article originally published, the name Ton Rijnders was misspelt, and the number of options notices that have been triggered was incorrectly reported. These errors have been corrected in the online and PDF versions of the article.

European Lead Factory hits its stride.

A large European drug discovery consortium is making inroads into novel chemical and biological space.

A metal-catalyzed enyne-cyclization step for the synthesis of bi- and tricyclic scaffolds amenable to molecular library production.

A facile metal-catalyzed diversification step for the synthesis of novel bi- and tricyclic scaffolds from enyne substrates is reported in this study. From a single starting material, topologically diverse scaffolds for library synthesis can be generated and decorated in a few steps. The methodology was used to produce a library of 490 compounds within the European Lead Factory (ELF) Consortium.

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

Synthesis of (Arylamido)pyrrolidinone Libraries through Ritter‐Type Cascade Reactions of Dihydroxylactams

AbstractThe Ritter‐type reaction of arylnitriles and N‐acyliminium ions generated in situ from dihydroxy‐γ‐lactams gave tetrahydropyrrolo[2,3‐d]oxazol‐5‐ones in excellent yields. A subsequent acidic hydrolysis in EtOH/H2O/TFA (trifluoroacetic acid) yielded new (arylamido)pyrrolidinones with excellent cis diastereoselectivity. A combined one‐step Ritter–hydrolysis procedure proved to be of equal efficiency. This versatile method, which was successfully used for the construction of a screening library containing 706 molecules within the European Lead Factory consortium, provides a simple way to access new compounds incorporating an arylamido and a pyrrolidinone moiety, both of which are widely found in marketed drugs and in biologically active molecules.

Exploitation of the Ugi–Joullié Reaction in the Synthesis of Libraries of Drug-Like Bicyclic Hydantoins

A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi–Joullié reaction/cyclisation sequence was exploited as the key complexity-generating process in which trifluoroacetic acid was employed as synthetic equivalent for chloroformic acid. Exemplar diversification of the bicyclic scaffolds was performed to enable subsequent translation to the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory.

Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries

The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug discovery-relevant chemical matter, the design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries is described.

Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library

A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European lead factory consortium for various biological screenings.

Branching cascades provide access to two amino-oxazoline compound libraries

An efficient synthetic access to two amino-oxazoline compound libraries was developed employing the branching cascades approach. A common precursor, that is, chromonylidene β-ketoester was transformed into two different ring-systems, that is, the pyridine and the benzopyrane substituted hydroxyphenones. In further two steps, the ketone moiety in two ring-systems was transformed into an amino-oxazoline ring. The functional groups on the two amino-oxazoline scaffolds were exploited further to generate, a compound collection of ca. 600 amino-oxazolines which are being exposed to various biological screenings within the European Lead Factory consortium.

Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.

MCR synthesis of a tetracyclic tetrazole scaffold

Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.

Concise Synthesis of Tetrazole-keto-piperazines by Two Consecutive Ugi Reactions.

AbstractA concise route for the synthesis of the novel compound class tetrazole–diketopiperazines was developed. The approach involves the use of two multicomponent reactions: the Ugi tetrazole four‐component reaction (4CR) and the classical intramolecular Ugi 4CR. The tetrazole–diketopiperazines comprise analogs of and are bioisosteric to bioactive diketopiperazines, which thus draws attention for novel bioactive compound design. This scaffold was produced to fill the screening deck of the European lead factory.

The Joint European Compound Library: boosting precompetitive research

The Joint European Compound Library (JECL) is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation. The JECL has been established with a core of over 321,000 compounds from the proprietary collections of seven pharmaceutical companies and will expand to around 500,000 compounds. Here, we analyse the physicochemical profile and chemical diversity of the core collection, showing that the collection is diverse and has a broad spectrum of predicted biological activity. We also describe a model for sharing compound information from multiple proprietary collections, enabling diversity and quality analysis without disclosing structures. The JECL is available for screening at no cost to European academic laboratories and SMEs through the IMI European Lead Factory (http://www.europeanleadfactory.eu/).

European Lead Factory Launches

Abstract The European Lead Factory, a public–private initiative for drug discovery launched in February, is ramping up. Its partners—initially a consortium of 7 pharmaceutical firms, 10 small- to medium-size companies, and 13 academic and nonprofit participants—will have access to approximately 500,000 chemical compounds and an ultra-high-throughput screening center.

European Lead Factory opens for business

Seven pharmaceutical companies and the Innovative Medicines Initiative have launched a €196 million project in a bid to boost academic and industry lead discovery.

IMI's leadoff hitter

Europe's Innovative Medicines Initiative has recruited 7 pharmas to each contribute up to 50,000 compounds from their proprietary libraries for a public-private partnership called the European Lead Factory. The pharmas will have access to an expanded chemical space and academic members of the factory will be able to run experiments with high-quality molecules.