Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

Petersen, L.; Blakskjær, Peter; Chaikuad, A.; Christensen, Allan; Dietvorst, Judith; Holmkvist, Johan; Knapp, Stefan; Kořínek, Marek; Larsen, Lesley; Pedersen, Anna-Kathrine; Röhm, Sandra; Sløk, Frank A.; Hansen, Nils Jakob Vest

doi:10.1039/c6md00241b

Cited by 72 publications

(67 citation statements)

References 32 publications

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“…Using YoctoReactor™ technology, scientists at Vipergen have described the synthesis of a linear library containing >12 million compounds, resulting from three series of acylation, reductive amination and urea formation steps. The library allowed the isolation of a MAPK14 inhibitor with potency in the single-digit nanomolar range in cellular assays (84) [Figure 9h]…”

Section: Library Design Chemical Reactions and Hit Compoundsmentioning

confidence: 99%

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

Neri

Lerner

2018

Annu. Rev. Biochem.

309

272

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The discovery of organic ligands that bind specifically to proteins is a central problem in chemistry, biology, and the biomedical sciences. The encoding of individual organic molecules with distinctive DNA tags, serving as amplifiable identification bar codes, allows the construction and screening of combinatorial libraries of unprecedented size, thus facilitating the discovery of ligands to many different protein targets. Fundamentally, one links powers of genetics and chemical synthesis. After the initial description of DNA-encoded chemical libraries in 1992, several experimental embodiments of the technology have been reduced to practice. This review provides a historical account of important milestones in the development of DNA-encoded chemical libraries, a survey of relevant ongoing research activities, and a glimpse into the future.

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Section: Library Design Chemical Reactions and Hit Compoundsmentioning

confidence: 99%

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

Neri

Lerner

2018

Annu. Rev. Biochem.

309

272

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“…The YoctoReactor has been used to generate libraries comprising more than 10 7 unique members. 47 This method, as well as a related approach described by Cao and co-workers, 41 simplifies adapter design by decoupling the DNA domain encoding BB identity from that directly involved in DNA templating ( Figure 10 c). However, in both cases a BB requires a different adapter for each position in the product.…”

Section: Combinatorial Synthesis By Dtsmentioning

confidence: 99%

The Evolution of DNA-Templated Synthesis as a Tool for Materials Discovery

2017

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ConspectusPrecise control over reactivity and molecular structure is a fundamental goal of the chemical sciences. Billions of years of evolution by natural selection have resulted in chemical systems capable of information storage, self-replication, catalysis, capture and production of light, and even cognition. In all these cases, control over molecular structure is required to achieve a particular function: without structural control, function may be impaired, unpredictable, or impossible.The search for molecules with a desired function is often achieved by synthesizing a combinatorial library, which contains many or all possible combinations of a set of chemical building blocks (BBs), and then screening this library to identify “successful” structures. The largest libraries made by conventional synthesis are currently of the order of 108 distinct molecules. To put this in context, there are 1013 ways of arranging the 21 proteinogenic amino acids in chains up to 10 units long. Given that we know that a number of these compounds have potent biological activity, it would be highly desirable to be able to search them all to identify leads for new drug molecules. Large libraries of oligonucleotides can be synthesized combinatorially and translated into peptides using systems based on biological replication such as mRNA display, with selected molecules identified by DNA sequencing; but these methods are limited to BBs that are compatible with cellular machinery. In order to search the vast tracts of chemical space beyond nucleic acids and natural peptides, an alternative approach is required.DNA-templated synthesis (DTS) could enable us to meet this challenge. DTS controls chemical product formation by using the specificity of DNA hybridization to bring selected reactants into close proximity, and is capable of the programmed synthesis of many distinct products in the same reaction vessel. By making use of dynamic, programmable DNA processes, it is possible to engineer a system that can translate instructions coded as a sequence of DNA bases into a chemical structure—a process analogous to the action of the ribosome in living organisms but with the potential to create a much more chemically diverse set of products. It is also possible to ensure that each product molecule is tagged with its identifying DNA sequence. Compound libraries synthesized in this way can be exposed to selection against suitable targets, enriching successful molecules. The encoding DNA can then be amplified using the polymerase chain reaction and decoded by DNA sequencing. More importantly, the DNA instruction sequences can be mutated and reused during multiple rounds of amplification, translation, and selection. In other words, DTS could be used as the foundation for a system of synthetic molecular evolution, which could allow us to efficiently search a vast chemical space. This has huge potential to revolutionize materials discovery—imagine being able to evolve molecules for light harvesting, or catalysts for CO2 fixation.The field of DTS ha...

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“…A highly specific 7 nM inhibitor of mitogen-activated protein kinase 14 (MAPK14, also called p38-a kinase) [58] was identified by Vipergen using a yoctoReactor TM DECL. The library consisted of three sets of building blocks (two sets of amino acids and one set of carboxylic acids) and had a size of 12.6 million members [18].…”

Section: Ligands Isolated From Dna-encoded Chemical Librariesmentioning

confidence: 99%

DNA‐encoded chemical libraries – achievements and remaining challenges

et al. 2018

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Edited by Wilhelm JustDNA-encoded chemical libraries (DECLs) are collections of compounds, individually coupled to DNA tags serving as amplifiable identification barcodes. Since individual compounds can be identified by the associated DNA tag, they can be stored as a mixture, allowing the synthesis and screening of combinatorial libraries of unprecedented size, facilitated by the implementation of split-and-pool synthetic procedures or other experimental methodologies. In this review, we briefly present relevant concepts and technologies, which are required for the implementation and interpretation of screening procedures with DNA-encoded chemical libraries. Moreover, we illustrate some success stories, detailing how novel ligands were discovered from encoded libraries. Finally, we critically review what can realistically be achieved with the technology at the present time, highlighting challenges and opportunities for the future.

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Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

Abstract: A DNA-encoded small-molecule library was prepared using yoctoReactor technology followed by binder trap enrichment to identify selective inhibitors with nanomolar potencies against p38α MAP kinase.

Cited by 72 publications

References 32 publications

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

The Evolution of DNA-Templated Synthesis as a Tool for Materials Discovery

DNA‐encoded chemical libraries – achievements and remaining challenges

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