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Director’s Blog: Wanted: A Few Good Assays

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There has been much concern over the fate of medication development for mental disorders. Some have complained that there are no truly novel medications coming from the pharmaceutical companies in the past three decades. Others have worried that the recent departure of pharmaceutical companies from psychiatric medication development presages a long draught with no new medical treatments likely. Meanwhile results from the large NIMH-funded comparative effectiveness trials, like CATIE and STAR*D, remind us of the need for a new generation of medications. At NIMH, we have been discussing how we might catalyze the next generation of drug discovery and development. One way, we believe, is by creating assays to probe new molecular targets relevant to mental disorders and to screen for new medications. Judging from recent progress, this approach looks hopeful.

Just this week, the National Library of Medicine’s Bookshelf website posted Probe Reports from the Molecular Libraries Program  . This “book,” from the NIH Common Fund’s Molecular Libraries Program  (MLP), will continually add “chapters” about the most promising probes and the assays used to discover them. The MLP’s Molecular Libraries Production Centers Network  provides public sector researchers with the infrastructure needed for compound libraries, robotics, informatics and other resources. These centers have already used over 350 assays to screen the Program’s repository of 370,000 small molecules. The Program, which is co-administered by NIMH and the National Human Genome Research Institute, continues to seek novel assays relevant to CNS disorders.

At the recent Society for Neuroscience meeting in San Diego, the MLP sponsored a satellite symposium on “Discovery of Molecular Probes.”  The presenters, grantees Drs. Roger Tsien  and Jeffrey Conn  , spotlighted opportunities for discovery by exploiting advances in high throughput screening using robotics and the principles of chemical biology. Such hi tech approaches are offering shortcuts to addressing some of our most pressing challenges.

To date, the MLP Centers have advanced a number of probes into early stages of drug development. Prominent among these successes is a promising target for medications to treat multiple sclerosis  (MS). NIMH grantee Dr. Hugh Rosen  , of the Scripps Research Institute’s MLP-funded Comprehensive Center for Chemical Probes Discovery and Optimization, is also scientific co-founder of a biotech company that is developing a compound derived from a MLP-discovered probe for MS, for which clinical trials are planned for next year.

The Society for Neuroscience meeting also featured another MLP success story. A research team led by Dr. Craig Lindsley  , of the NIMH-administered, MLP-funded Specialized Chemistry Center for Accelerated Probe Development at Vanderbilt University, reported a new tool for understanding the role of a receptor subtype that has been implicated in the thinking deficits of schizophrenia and Alzheimer’s disease. This new compound  binds to the M1 acetylcholine receptor, which plays a pivotal role in learning and memory among other functions. In the new study, it reduced seizures in mice while sparing cognition, suggesting potential applications in disorders like Parkinson’s disease, epilepsy and fragile X syndrome. The compound is currently in the drug discovery stage.

Beyond the Molecular Libraries Program, the NIMH has also recently sought proposals to develop a new generation of “disease in a dish” assays for probing the workings of brain cells and molecules. The aim of this Scalable Assays for Unbiased Analysis of Neurobiological Function  program is to automate and standardize measures of small molecules, peptides or genes relevant to NIMH’s mission. These tools will ultimately help identify new therapeutic targets. For example, cells of interest from patient populations might be screened to identify molecular networks that could be the target of a new medication, as already done for cancer cells.

Similarly, a standing grant program, Development of Assays for High-Throughput screening for use in Probe and Pre-therapeutic Discovery , supported by NIMH and 8, other Institutes seeks proposals for clinically relevant assays for targets that may be indirectly related yet provide insight into the biology of disease – with an eye to identifying new targets for therapies. NIMH is particularly interested in such probes that might help translate target discovery into new treatments for mental disorders. Such assays could emerge from genes or proteins implicated in animals or human disorders, or from clues to a medication’s possible mechanism of action. Potential targets include enzymes, receptors, epigenetic modifiers, and transcription factors. Cross-disciplinary collaborations are especially encouraged.

While there are many reasons to be concerned about the state of medication development for mental disorders, the abundance of new targets and powerful tools like high throughput screening give us good reason to be hopeful that we can catalyze this early phase of medication discovery. Along with repurposing currently available medications and creating more effective psychosocial treatments, NIMH is taking a broad and deep approach to developing better treatments for mental disorders.

References

NIH Funds Nine Centers to Speed Application of Powerful New Research Approach: Roadmap Network Will Produce Chemical Probes to Explore New Targets for Therapies  . NIH News, September 2, 2008.

Sphingosine 1-phosphate receptor signaling.  Rosen H, Gonzalez-Cabrera PJ, Sanna MG, Brown S.Annu Rev Biochem. 2009;78:743-68. Review.PMID: 19231986

Differential effects of allosteric M(1) muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation. 
Davis AA, Heilman CJ, Brady AE, Miller NR, Fuerstenau-Sharp M, Hanson BJ, Lindsley CW, Conn PJ, Lah JJ, Levey AI. ACS Chem Neurosci. 2010 Aug 18;1(8):542-551.PMID: 20835371

 

Robots screen small molecules for biological effects.

Robots screening small molecules at the NIH Chemical Genomics Center, Rockville, MD