The National Institutes of Health announced this week that it will funnel approximately $280 million over the next four years into a small-molecule screening program involving nine institutions that is aimed at advancing the use of chemical probes in research and medicine.
Coordinated along with the National Human Genome Research Institute and the National Institute of Mental Health, the Molecular Libraries Probe Production Centers Network initiative is the so-called production phase of the Molecular Libraries and Imaging Initiative, which began in 2004 under the NIH Roadmap for Medical Research initiative.
The MLPCN will screen a library of over 300,000 small molecules that are maintained in the Molecular Small Molecule Repository, which is located at the drug research company Biofocus DPI’s San Francisco headquarters.
The data the network generates will be made available through the National Library of Medicine’s PubChem database.
The MLPCN has four comprehensive centers and five specialized centers. The comprehensive centers receiving funding under the program are: The Burnham Center for Chemical Genomics, La Jolla, Calif.; Broad Institute Comprehensive Screening Center, Cambridge, Mass.; National Institutes of Health Chemical Genomics Center, Bethesda, Md.; and the Comprehensive Center for Chemical Probe Discovery and Optimization at the Scripps Research Institute, La Jolla, Calif.
The five specialized centers are the Johns Hopkins Ion Channel Center, Baltimore; Southern Research Specialized Biocontainment Screening Center, Birmingham, Ala.; University of New Mexico Center for Molecular Discovery, Albuquerque, N.M.; University of Kansas Specialized Chemistry Center, Lawrence, Kan.; and the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Nashville, Tenn.
“We are right at the beginning of the new production phase, where the centers within the network have the ability to operate at a full capacity,” said Linda Brady, project team leader for the Molecular Libraries initiative at the NIMH. The centers will implement a variety of assays, including cell-based, phenotypic, and enzyme receptor assays, and use them to screen the molecules in the Molecular Small Molecule Repository.
Out of the hits identified from those screens, the centers will undertake chemistry to optimize them to have activities and specificities for use in in vitro cell systems and preparations, Brady told CBA News this week.
“Already, between 50 and 60 percent of our assays are cell-based assays,” said Carson Loomis, project team leader for the Molecular Libraries initiative at the NHGRI, in an interview with CBA News this week. Unlike pharma companies, the NHGRI has a significant number of assays that are phenotypic, where initially scientists look at phenotypic changes in the cell, and then proceed using compounds both in and outside of the program to find a target.
Much of the first phase of the Molecular Libraries and Imaging Initiative involved building an infrastructure within each center in the network, hiring staff, and purchasing equipment. “This production phase gives us the opportunity to build on the successes that we built during the initial three-year phase, to demonstrate the efficiency and the effectiveness of that infrastructure, and really make some serious headway in producing a good number of high-quality chemical probes,” Christopher Austin, PI on the grant for the NIH Chemical Genomics Center and the director of the CGC, told CBA News.
He went on to say that the CGC was “the original center in the MLPCN, so we will be doing pretty much what we have been doing the last four years.”
MLPCN comprehensive centers will be working with investigators throughout the academic community to develop assays of novel biology and disease states and get those assays approved through the network’s peer review mechanism.
“Already, between 50 and 60 percent of our assays are cell-based assays.”
“Then we will get them into the center and work with our collaborators to develop chemical probes of the biological system in which they are interested,” said Austin.
The CGC will be using its $50.8 million MLPCN grant to do about 25 assay projects per year. “This production phase period also allows us to do some special technology-development projects that, in our case, are focused on chemical informatics, and making these data accessible and usable and minable by the community,” Austin said. Part of the grant provides for that, separate from the production that the CGC will be doing.
The CGC has been working with a large number of individual investigators around the country, according to Austin. “We get about two or three calls a week from new investigators who want help from us to develop an assay of a novel biological pathway or target,” he said.
The CGC has been working with these investigators to develop assays over the last year or two, and they have been submitted to the MLPCN network for peer review, but they have not been officially approved yet, because the network was not approved.
“Our next immediate step is getting those assays assigned to us and being able to work actively with those collaborators to do some really good biology, and decipher what the genome is made of using those chemical probes,” Austin said.
The Burnham Institute announced this week that as part of the MLPCN program, it was awarded a $97.9 million grant from the NIH. “We will be doing about 25 high-throughput screening campaigns per year. We hope to generate about 15 chemical probes from those campaigns, which would then be available to the research community for use as tools,” John Reed, Burnham president and CEO, told CBA News this week.
He added that Burnham’s grant has a technology-development component, which involves developing technologies for high-content cell-based imaging. “We are developing new software [and] hardware for [imaging], as well as new culture systems to do 3D cultures and 3D imaging,” said Reed, who is also the director of the Burnham Center for Chemical Genomics.
Burnham and the other MLPCN centers are responsible for specific milestones and deliverables every year. These milestones are negotiated with the NIH. “We will be judged by NIH on an annual basis based on our performance against the goals. They adjust our budget annually up or down based on our performance,” Reed said.
For example, Reed said that Burnham has to complete 22 HTS campaigns and file 10 probe reports in the first year. These are reports where the center identifies a chemical that has been optimized to certain standards of potency and selectivity for use as a research tool.
Reed said that other examples of deliverables for which Burnham is responsible include developing a tool box of “organotypic” 3D systems for screening, as well as image acquisition [and] analysis tools for screening 3D models.
“There are at least 10 milestones for our center,” said Reed.
The Broad Institute was awarded an approximately $86 million grant through the MLPCN initiative that will allow it to drive the probe discovery effort as part of the MLPCN, Stuart Schreiber, professor of chemistry at Harvard and director of chemical biology at the Broad Institute, told CBA News. Schreiber said that the money will “support chemistry, screening, optimization, and data analysis, with our mission being to make all of our results publicly available.”
The institute will use the funds to do chemistry, small-molecule screening, optimization, and data analysis to create on the order of 12 to 15 small-molecule probes per year, over a six year period.
The Southern Research Institute will use its $14.7 million in funding as one of the MLPCN’s specialized centers, “because of our expertise in infectious diseases and our capabilities to test compounds against live pathogens,” said Wilson Blaine Knight, the institute’s vice president for drug discovery. SRI can run those screens in high-containment labs, such as BSL 2 or BSL 3.
Knight went on to say that although SRI has internal expertise in a number of infectious disease areas, as part of the MLPCN, it will be prepared to conduct high-throughput screening against any infectious diseases. “The funds will go toward running up to five HT screens per year,” Knight said.
This production phase comprises the final part of the Molecular Libraries and Imaging initiative. “The requirements for the Roadmap are that you can have up to two periods of funding for up to a total of 10 years. At the end of this period of funding, the Molecular Libraries program will have reached that endpoint,” said Austin. One of the things that the network centers will be doing towards the end of this six-year funding period is determining which NIH institutes are going to fund the centers going forward.
“Our hope is that the funding will be forthcoming from individual NIH institutes or, what is more likely, from groups of NIH institutes that get together to fund these centers,” Austin said.
In terms of the funding received by other members of the MLPCN, Scripps received more than $80 million, Johns Hopkins received $16.2 million, the University of New Mexico received $15.5 million, Vanderbilt received $17.4 million, and the University of Kansas received $20.2 million.