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Target Practices

By Ryan DeBeasi

January 20, 2010
| At CHI’s Discovery on Target conference* last November, presenters discussed a variety of ways to speed drug development, improve efficacy, and avoid side effects. 

Michael Dabrowski, head of AstraZenica R&D’s global ion channel initiative, discussed ways to screen more rapidly as well as the lower-tech—but equally important—topics of management and communication. He noted that there is still much to be learned: “The ion channel is a teenager compared to the kinases and GPCRs.”

On the technology front, he discussed the Dynaflow HTC automated patch clamping device, which let him quickly test compounds’ activity on ion channels at a variety of potentials. The device, which sped up screening and reduced the “cost per datapoint,” is slated for release in the second quarter of 2010.

On the communication front, Dabrowski discussed a simple but effective idea: “postcards from the lab.” These email “postcards” are single slides that succinctly explain discoveries to researchers in the company. Readers who want to learn more can click a link to view a complete presentation. The slides are sent to almost everyone in the company’s R&D department. At a company of some 65,000 people, such initiatives can be very helpful.

Also covered was an “impact grid” that described the effect of a discovery.  The vertical axis of the grid measured strategic, long-term, and perceived impact, while the horizontal axis measured short-term impact on actual projects.  This diagram could point out successes that might otherwise go unnoticed—for example, a set of assays that were discussed in a low-impact journal but were widely used.
He also gave management suggestions: have only one owner for a project, and avoid dispersing the team over many locations. He advised the audience to take a balanced approach to risk: “not every project should aim for moon landing,” he said.

Gregory Kaczorowski, adjunct professor at New Jersey Medical School and Robert Wood Johnson Medical School, said that although 15% of drugs target ion channels, it is difficult to avoid side effects. “You can be fooled working with rodents and then going to humans,” he said. Screening can be time-consuming, “you’re really trying to find the needle in the haystack,” he said.

Kaczorowski discussed research on a drug intended to stop neuropathic pain by blocking sodium channels. The drug was similar to lidocane, he said, but side effects on the central nervous system (CNS) had limited related drugs’ usefulness. To avoid such issues, the new drug had to specifically target on particular sodium channel (Nav 1.7).  Inhibition of a related channel (Nav 1.5), for example, could cause cardiac side effects. Kaczorowski used Fluorescence Resonance Energy Transfer (FRET) using litmus-like dyes that turned red or blue depending on the potential across the neuron membrane.  When a compound successfully blocked the channel, Kaczorowski could see that the cell was not depolarized. “You can use this to screen a lot of compounds very quickly,” he said.

He also discussed ways to improve on ziconotide, a drug that blocks the Cav 2.2 ion channel, implicated in many types of pain. The drug worked well but had a low therapeutic index. Rather than rely on electrophysiology (too slow), he controlled potassium concentrations to modify neurons’ resting potential. Some compounds were more effective at certain potassium levels than others—a drug might be very effective when the cell is polarized but ineffective when the cell is hyperpolarized. Kaczorowski said that he doesn’t expect conventional electrophysiology to ever go away, however it’s still needed to validate results.

Eric Verdin, professor of medicine at the University of California, San Francisco, discussed histone deacetylases (HDACs), which are implicated in cancer and CNS disorders such as Alzheimer’s disease. HDAC inhibitors can regulate genes by preventing the removal of acetyl groups from the proteins involved in their transcription. HDAC inhibitors can be effective anti-tumor agents, but they have not been successful so far because they are poorly understood. Factors such as diet and alcohol can influence the activity of HDAC inhibitors by increasing levels of aceytl-CoA. This compound can promote hyperacetylation. In addition, polyamines, a type of ion that is bound to RNA and DNA, can affect the activity of HDAC inhibitors. With low levels of polyamines, programmed cell death is more frequent, cell growth is reduced, and several types of HDAC inhibitors are less effective. Such interactions should be considered during development, he said.
Scottish Biomedical, a CRO, announced its HDAC drug discovery panel in October. Business development manager Morag Nelson said the company can provide HDAC enzymes, develop assays, screen for HDAC inhibitors, or handle the whole process. She estimated that about 20% of HDAC clients choose the last option. Scottish Biomedical couldn’t compete with China for general chemistry outsourcing but expects to differentiate itself with this specialized service. The company has received more work from large pharmaceutical companies in the past year, as some companies have laid off entire departments. Nelson expects to see applications beyond oncology as research on HDAC inhibitors progresses. 

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