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Genedata Screener Paper Highlights 2018

December 11, 2018
Genedata

We are looking back on some of the great work that was done by the Genedata Screener community in 2018. 

Parkinson's Drug Kinetics

Drugs targeting dopamine receptors could help treat Parkinson’s or neuropsychiatric disorders. But to make effective drugs it’s important to understand drug kinetics. To do just this, de Witte et al. use mechanistic analysis to look at how dopamine drugs bind and dissociate from targets, and how this relates to cellular signaling. With computer modeling they looked at how these drugs might affect dopamine dynamics, giving possible insight into the therapeutic windows or side effects.1

Drug Repurposing

Bringing a new therapy to market is incredibly costly. Drug repurposing can help reduce these costs. Read our short article discussing a resource that scientists at the California Institute for Biomedical Research have developed to enable organizations of all kinds to perform drug repurposing screens.2

Testing Drug Toxicity

Our partners at AstraZeneca continue to pioneer the use of micro-sized, 3D models of cardiac tissue to test drug toxicity. They do high-content screening on these models, saving valuable time, money and effort by overcoming limitations of less realistic  models. We previously posted about AstraZeneca’s work using high-throughput, high-speed imaging to measure contractility in these models. In their latest paper, they detect structural damage using cell viability markers.3

3D model of cardiac tissue (Source: AstraZeneca)
Screening Ion Channels

Ion channels play a role in a range of diseases including pain, epilepsy, and cardiac arrhythmia. Therapies need to target unique channel subtypes, without unwanted non-specific effects. This is hard, because subtypes often resemble one another. To meet this challenge, Chernov-Rogan et al. from Genentech screened 1 million compounds to find a new class of Nav1.7 inhibitor. Like other channels, Nav1.7 gates movement of ions across membranes, generating membrane potential. This is needed for neurons to signal and heart cells to contract, for example. Typical screening assays involve activating Nav1.7 with molecules that bind the channel’s “passageway” or pore, but this tends to yield nonspecific, pore-binding hits. By changing the activator and tweaking the Nav1.7 pore itself, the scientists optimized the assay to detect more selective drugs. This was an impressive screen employing 1,536-well fluorescent assays and automated patch-clamp electrophysiology (SynchroPatch, Nanion®) to assess >9,000 primary hits.4

Targeting Autophagy

Autophagy is a cell’s “waste disposal system”. Parkinson’s, ALS, Huntington’s, metabolic disorder, are all linked to autophagy malfunction, but current drugs to restore normal function aren’t specific. Chiang et al. from UTSW did a high-throughput screen on over 300,000 compounds from the UTSW and Broad Institute libraries, finding drugs that selectively target a protein interaction important in autophagy. For their screen, they developed two luminescent assays for interaction between these proteins, Beclin1 and Bcl2. For the primary screen, they used a split firefly enzyme. When the proteins interact, the halves of the enzyme reunite, and its activity generates a light signal. To confirm hits, the scientists used an AlphaLISA® (Perkin Elmer®) assay, where upon protein interaction, tiny latex beads get close enough to excite one another with oxygen and emit light. The authors home in on three candidate drugs with greater selectivity for autophagy.5

Cell Line Variability

Why can it be so hard to turn HTS screening hits into successful cancer therapies? In crucial work, Ben-David et al. the Broad Institute of MIT and Harvard showed that one reason could be cell line variability, as lines accumulate genetic aberrations, generation over generation in different labs under various conditions. Check out our short article on what this means for drug screening efforts.6

We hope you’ve enjoyed reading this series of highlights on work done by the Genedata Screener community in 2018. To see more work being done by Genedata users, see our Resources pageThank you again to our users and customers, and we wish you a Happy New Year!

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References:

1. de Witte et al. "In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations". British Journal of Pharmacology 21:4121-4136 (2018)

2. Janes et al. "The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.Proceedings of the National Academy of Sciences of the USA 115:10750-10755 (2018)

3. Archer et al. "Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology." Scientific Reports 8:10160 (2018).

4. Chernov-Rogan et al. "Mechanism-specific assay design facilitates the discovery of Nav1.7-selective inhibitors." Proceedings of the National Academy of Sciences of the USA 115:E792-E801

5. Chiang et al. "High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding." ACS Chemical Biology 13:2247-2260.

6. Ben-David et al. "Genetic and transcriptional evolution alters cancer cell line drug response." Nature 560:325-330 (2018)