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Feature Articles : Apr 15, 2008 ( )
HTS Carving Out Hit-to-Lead Position
Researchers Are Coupling this Technology with Other Methodologies to Enable Better Screening
Pressure to discover more hits and develop more blockbuster drugs with less time and expense spent on target screening continues to spur companies to invest in high-throughput technologies earlier in the drug discovery process. In addition, there is a trend toward combining cell biology, imaging, and in vivo experimentation skills. Firms presented their newest screening methods at the recent “Screening Europe 2008” conference in Stockholm.
Drug screening against GPCR targets continues to be a major focus for many companies, accounting for more than 60% of prescription drugs currently on the market.
Researchers at Acadia Pharmaceuticals use its high-throughput screening platform, R-SAT® (receptor selection and amplification), to screen GPCRs, RTKs, and nuclear hormone receptors for targets. This platform is a cell-based assay where genes are transferred to cultured cells. Functional activities of the potential targets are evaluated via signal-transduction pathways that trigger cellular growth. Marker gene technologies are used to report the growth signals.
“This is a homogenous assay that allows you to better understand the pharmacology around GPCR targets,” noted Fabrice Piu, Ph.D., director, clinical genomics. “It also integrates all the signaling pathways that emanate from the receptor based on the action of the ligand. It detects any chemistries that have direct interaction between the receptor and the ligand.”
The technology also enables the identification of new mechanisms of action. Dr. Piu presented two examples of this. The first was that inverse agonism at the 5-HT2A receptor predicted antipsychotic activity. One agonist, pimavanserin, is currently in Phase III trials for treating psychosis in Parkinson’s disease. The second example was that a metabolite of clozapine, ACP-104, is a M1 muscarinic agonist. This suggested that it may have cognitive benefits. It is currently in a Phase II trial for schizophrenia.
“Frozen cells are very much the industry trend at the moment,” according to Bob Kendall, Ph.D., development scientist at GE Healthcare Life Sciences. “Researchers are adopting cryopreserved cells for a number of assays, and it seems to be the goal to convert all assays to a frozen-cell format.” The main advantage, he added, is that it decouples scheduling of large batches of cells from actual screening and improves assay performance by eliminating batch-to-batch variation.
One major roadblock in the drug discovery pipeline is whether a compound will be effective in a patient. “Our screening service can determine in preclinical stages whether a drug being developed interacts with other receptors that may cause side effects,” explained Blaine Armbruster, Ph.D., product manager at Millipore.
Merck Serono has been involved in a research effort with the WHO since 2004 to develop leads for neglected diseases like malaria and sleeping sickness. Academic groups suggest potential drug targets that are then forwarded to the company for screening.
Instead of focusing on the traditional, druggable targets, Avalon Pharmaceuticals developed a screening platform, HITS® (high-throughput integrated transcriptional screen), that allows for blind, initially hypothesis-free screening to discover targets and access novel mechanisms of action in key disease pathways, according to Reinhard Ebner, Ph.D., principal scientist.
Integrating HTS and Profiling
Researchers at the Novartis Institutes for BioMedical Research developed a protease platform that combines biology, medicinal chemistry, and structural biology. It enables target validation, protein production, assay development, protein crystallization, hit finding, hit validation, hit-to-lead chemistry, and lead optimization.
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