DNA-Encoded Library (DEL) technology is an increasingly prominent drug discovery approach based on simultaneous screening of potentially huge numbers of compounds against a protein target of interest in a general binding assay. Each compound is tagged with a unique DNA strand which functions as an identifying barcode. Compared to more traditional high-throughput screening approaches, DEL operates at significantly reduced costs, creating new opportunities for drug discovery groups of any organizational size.<br/>We have developed the first application of a dynamic DEL system, wherein two DNA strands featuring universally complementary annealing regions can be randomly combined to present two binding moieties to the target, with the DNA interactions designed to be intrinsically unstable, driving constant reshuffling of the molecular pairs until they are stabilized by sufficiently strong binding to the protein target. This system was designed to overcome limitations in library construction and data quality, allowing the preparation of equimolar libraries without side products or truncates.<br/>Benchmarking this platform against a conventional system showed over 30 times improved signal-to-noise ratios with reduced false positive rates. Using this platform, we have created multiple libraries based on both fragment and small molecule moieties, offering over 120 million highly diverse and medicinally relevant compounds for discovery which we have deployed against a broad range of targets, including proteases, cytokines, multiple enzyme families and GPCRs.<br/>Here we present results of hit discovery and validation using our platform against the human motor protein kinesin-1. Targeting of kinesin family proteins is of interest due to implications in both cancer and neurodegenerative disease. Application of our platform revealed hits which were investigated in a functional assay to reveal multiple structurally separated inhibitors, as well as an activator. Of particular interest is the activator, which is the first known direct activator of kinesin-1.

Dynamic DNA-encoded library technology: Discovery of kinesin-1 activators and inhibitors

2019 Spring National Meeting

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