High-throughput screening platform for cancer drug discovery
Details
Rockville, MD USA. Date of Talk: 2017-12-06
Speakers
Recht, Michael I.
Jacob Chamoun
Pattekar, Ashish V.
Farzaneh Afshinmanesh
Event
High-throughput screening platform for cancer drug discovery
Motivation: High-throughput screening (HTS) campaigns have often relied on assays using labeled ligands or enzyme substrates. Artifacts associated with labeling have led to the erroneous identification of compounds that act in on the labeled substrate rather than the intended target. A label-free, solution-based HTS method will facilitate identification of compounds acting specifically on the intended targets. Technology: The goal of this proposed research is to develop a spectro-optical calorimetry (SPOC) technology that will enable the use of calorimetry in high-throughput screening of compound libraries against cancer therapeutic targets. SPOC has the potential to enable label-free thermodynamic characterization of binding and enzymatic reactions with uncompromised sensitivity at three orders of magnitude higher throughput and more than three orders of magnitude lower sample consumption than conventional microcalorimetry. The throughput could be two orders of magnitude higher than state-of-the-art nanocalorimeters and would be significantly better than the throughput of 1536-well plate assays when accounting for its need for assay development for new targets. Progress Highlights: We are currently developing the first research prototype of this system. We have characterized the temperature-dependent optical properties of thermochromic liquid crystal microparticles in ensembles of 500 picoliter droplets in microfluidic chips. Reactions with reference compounds (barium chloride/18-crown-6; calcium chloride/EDTA) are currently in progress and will be compared to results obtained with a standard microcalorimeter. Modeling of the thermal behavior of droplets in the microfluidic chip has been performed. Next steps: The temperature regulation of the microfluidic chip will be improved, the optical detection system will be optimized to enable measurement of temperature changes of droplets travelling along the entire length of the microfluidic channel, and reactions of proteins with small molecules will be measured.
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