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The NIH's Molecular Libraries Program - What's Next?

The National Institutes of Health's Molecular Libraries Program is ending. Was it a success? Did it fail to live up to its expectations? It depends on who you ask.


The Molecular Libraries Program (MLP) was created in 2003 to offer public sector biomedical researchers access to the large-scale screening capacity necessary to identify small molecules that can be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. The funding came from the NIH Common Fund, which is coordinated by the Office of Strategic Coordination within the Office of the NIH Director.

The NIH said that the goal for the MLP was to "facilitate the development of new drugs, by providing early stage chemical compounds to researchers in the public and private sectors for validation of new drug targets, which could then move into the drug-development pipeline. This model of drug development may be particularly useful for rare diseases and areas of unmet medical need, which may not be attractive for development by the private sector."

In 2005, the Molecular Libraries Screening Centers Network (MLSCN) was launched as part of the MLP. Its goal was to expand the availability and use of chemical probes to explore the function of genes, cells, and pathways in health and disease, and to provide annotated information on the biological activities of compounds contained in the central Molecular Libraries Small Molecule Repository in a public database named PubChem.

The NIH expanded the program from its pilot phase in 2008. Today the program consists of four large screening centers, which included the NIH's Geonomic Center and five supporting centers. They have produced more than 240 probes, one of which is now in a Phase 1 clinical trial as a multiple sclerosis drug.

Probe Guidelines v2.0

A MLSCN probe is a compound which represents an improvement over the existing art. Supporting information is required showing currently available probes, their properties and how the new probe is clearly an improvement [first or best in class]

Potency: Criteria for potency is context dependent, varying with the assay and target type, and current state of the art. In general, probes identified via biochemical assays are expected to exhibit potencies of < 500nM and, more ideally in the 100nM range. Those identified in cell based assays are expected to exhibit potencies at a level of < 1microM, however in certain instances potencies in the 10microM may be acceptable. Criteria for whole organism screening is less stringent.

Solubility: sufficient solubility in relevant solvents

Availability: the probe molecule should be accessible in amounts to allow advanced studies (15-20mg), and protocols for its preparation or isolation should be made available

SAR, mode of action (e.g. evidence of binding to target, characterization of mechanism of action) and awareness of selectivity against relevant and/ or related targets is expected

Appropriate data on toxicity, permeability, etc. of probes are strongly encouraged

The funding for the $100 million dollar a year program is coming to an end. The last full-year of funding was in 2011. "The program tapers off to 66% of full funding in 2012 and 33% of full funding in 2013. All of the funds will be disbursed by May 2014," according to Carson R. Loomis, Ph.D., program director, Molecular Screening Libraries, National Human Genome Research Institute. But the NIH will still be very involved with the MLP.

On December 23, 2011, President Obama signed a spending bill that includes $30.7 billion for NIH and establishes the National Center for Advancing Translational Sciences (NCATS). "The NIH Chemical Genomics Center will become part of the NCATS. The other member centers have been invited to find support at individual NIH Institutes," Loomis said.

Although Loomis notes that there has been criticism of the MLP, he says the MLP was a great success. "The program has surpassed all of its goals. It has generated valuable data, freely available to all, and has brought basic science to the search for new medicines and biochemical probes."

But there are skeptics, especially those in the drug industry, who question whether the program has been cost effective and believe that the majority of the probes discovered are of questionable value. Even those who support it agree that the screening centers took longer than expected to set up and that the goals were not clearly defined.

Derek Lowe, author of In the Pipeline, has called the MLP the program no one wants. In a recent blog post titled "Does Anyone Want the NIH's Drug Screening Program?" he wrote, "I know there are readers out there from both sides of this particular fence, I'd be interested in hearing some comments. Has the screening initiative been worthwhile? Should it be kept up – and if so, how?

One of his readers wrote "the problem was that the program focused too much on quantity over quality – the screening centers were graded/funded solely on the number of "probes" meeting original criteria (Usually IC50 cutoffs and an antitarget) and not on the quality of what was produced."

Loomis says the critics are focusing on the wrong measurements. "If they were looking for breakthrough drugs coming out of the program, I can understand their frustration. But these were not the goals of the program. Our goal was the early discovery of compounds to aid in the advancement of science, not to mimic pharmaceutical industry's search for a new drug. If we were able to advance the knowledge of how a protein works that was the ultimate goal. But learning whether a particular protein did not work is valuable information as well. Knowing what road not to pursue (in treatment of a disease) can save time and precious resources."

Mission Accomplished Says the NIH

Loomis counts among the MLP successes:

• One compound is in a Phase I trial. The compound (an S1P1 receptor agonist with novel receptor interactions), was discovered by the Scripps Research Institute in San Diego, CA and has the potential for the treatment of multiple sclerosis and other autoimmune diseases.

• The hiring of chemists from pharmaceutical companies. This brought in chemists who had experience with the drug approval process and brought that skill set to the MLP teams.

• Helping to establish PubChem as a resource that now has 50,000 hits a day. The majority of its content comes from the Molecular Libraries.

High input screening through robots which has led to rapid screening. It is cost-productive and eliminates human error. It has led to the generation of over 6 million CRCs from > 120 assays in the last three years and is a technology that can be widely implemented to increase efficiency of screening and lead generation.

• The establishment of the MLP helped to increase the number of academic centers devoted to drug discovery.

Loomis supplied production numbers as of September 2011. "The Molecular Libraries Centers have accepted 547 probe discovery projects since the program began in 2004. By the end of 2011, 229 probes have been identified. Reports on the individual probes can be found in the NCBI Bookshelf and the associated screening and chemical data may be found in the PubChem database. During this period, the ML Centers published 487 scientific papers or reviews on the screening and chemistry resulting from work on these projects."

What Some Experts Think

John C. Reed, M.D., Ph.D. is the chief executive officer of Sanford-Burnham Medical Research Institute in La Jolla, CA. Their screening center receives about $16 million a year from the Common Fund. He is concerned that it will be very hard to replace the money once the NIH funding dries up. In an interview published in Science he said, "if there's not a long-term commitment to keep it available to the academic community, why did we make this hundreds of millions of dollars investment?"

Reed is hoping that the NIH's proposed National Center for Advancing Translational Medicine will spur the development of new drugs. But he notes that it does not address the funding cuts to the libraries.

SLAS Board Member William P. Janzen, director, Assay Development and Compound Profiling in the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina at Chapel Hill, says the MLP was a good idea, but there was concern about what would happen once the funding ended. "The problem for many of the Centers was that there was not sufficient funding to take them to sustainability. The recently released RFAs (requests for applications) will address some of these issues but they also open the field to much more competition; I would not be surprised to see some of the current centers change their models or even shut down."

G. Sitta Sittampalam, Ph.D. knows the MLP well, as a collaborator with The NIH Center for Chemical Genomics (NCGC), and currently NIH Center for Translational Therapeutics (NCTT), and as a reviewer for NIH grants on HTS assay development and screen implementation involving academic investigators. Until last month he was deputy director of the Institute for Advancing Medical Innovation (IAMI) at the University of Kansas Cancer Center and oversaw cancer drug discovery projects at the high-throughput screening laboratory (KU-HTS) at the Lawrence campus. In September 2008, Professor Jeff Aube at the University of Kansas received a six-year, $20.2 million research award from the NIH to establish a Specialized Chemistry Center (KU SCC) as part of the NIH Molecular Libraries Probe Production Centers Network. IAMI, KU-HTS and the KU-SCC have collaborated in developing a state–of-the-art HTS, drug discovery and drug repurposing projects based academic research at the University of Kansas.

Sittampalam is now a senior science officer at the Therapeutics for Rare and Neglected Diseases (TRND) program at NCTT. He says the MLP succeeded in creating an infrastructure for drug discovery within academic centers and also helped make transparent to the academics and the public how difficult the translational process is in real life. "Several of the probe molecules that have been discovered through the MLP (and the associated chemical and biological data) now publicly available on PubChem may provide the basis for novel therapeutics for major diseases, and for over 6,000 known rare and neglected diseases. The question is how to take this to the next level? This process requires expensive pre-clinical testing to translate these molecular probes into useful clinical candidates. There is no easy answer to this question."

Sittampalam is concerned about the effects on the individual screening and chemistry centers sponsored by MLP, as the current funding winds down. Many of these centers do not have sustainable business plans in place to replace the NIH funds. He predicts that of the existing centers only four will survive in their current form.

Alan D. Palkowitz, Ph.D., vice president of discovery chemistry research and technologies at Eli Lilly and Company, has noted a limitation of the MLP is its lack of focus on the desired end result. "It is very rare for a drug to come out of molecular screening. Pharmaceutical companies have more resources and more experience to advance primary findings to outcomes."

He credits the MLP with discovering several probes that show promise and giving the academic centers a better understanding of translational research in a focused way. But in Palkowitz's view, "simply screening molecules against biological targets is not enough. To further the understanding of molecules in disease you have to have the potential to ultimately test in humans. The molecular libraries initiative was never set up to do this."

He believes that the Lilly Open Innovation Drug Discovery Platform is an alternative model to the MLP for discovering potential new medicines. The Open Innovation Drug Discovery platform uses Lilly-developed disease-state assays and a secure web portal to evaluate the therapeutic potential of compounds synthesized in university and biotechnology laboratories.

Christopher A. Lipinski, Ph.D., spent most of his career at Pfizer. Before he retired in 2002, he was senior research fellow in the exploratory medicinal sciences department at the Pfizer Global Research and Development Groton Laboratories. Today he is on the scientific advisory board of Melior Discovery, Inc. He has questioned the quality of some of the medicinal chemistry coming out of academia, which he feels puts too much pressure on researchers to publish and not enough time given to discovery. "The goals of chemical biology and drug discovery are quite different with implications for the types of compounds one would like to screen."

Lipinski notes that when the screening library collection began the NIH had little medicinal chemistry experience. "I was a member of an early teleconference to discuss what types of compounds should be acquired by the NIH for high-throughput screening (HTS) to discover chemical biology tools and probes. Our teleconference group was about evenly split between industry people and academics. The academics talked about innovation, thinking out of the box, maximum chemical diversity and not being limited by preconceived rules and filters. The industry people talked about pragmatism, the lessons learned and about worthless compounds that could appear active in HTS screens. The NIH was faced with two irreconcilable viewpoints. They had to pick one and they chose the academic viewpoint."

In Lipinski's view, this was a mistake. As part of a group that did a crowd sourcing analysis of the value of the first 64 tools and probes from the NIH Roadmap screening effort, he said that "charitably about 75% of the probes had value; 25% were worthless." He notes that faced with disappointing early HTS screening data, the NIH moved away from the academic viewpoint to one more aligned with the industrial viewpoint and subsequently had better results.

Caroline Shamu, Ph.D., is the director, ICCB-Longwood Screening Facility at Harvard Medical School. Their research is not supported directly by the MLP. The ICCB Screening Facility was one of the first high-throughput screening facilities to be opened in an academic setting. Its highly successful Investigator-Initiated Screening Program has facilitated small molecule screening projects for more than 80 different research groups from throughout the U.S. and abroad.

As a person who does not work for NIH or the pharmaceutical industry and is not part of the MLP, Shamu notes that "the program began at a time when there was tremendous growth in our understanding of fundamental biology, spurred largely by insights into the genome and advances in molecular biology. The MLP is ending at a time when the NIH and industry are challenged by the economy and under pressure to produce new drugs."

She is concerned that if the MLP disappears, presumably the compound library that it established for screening will cease to exist/be dispersed. "If there is no funding to pay the compound repository to maintain the small molecule library, the library will no longer be available for purchase as a whole entity."

February 23, 2012