Since its creation, our Broad CMLD Library Synthesis Core has progressed through a series of technology platforms, incorporating insights gained from our own experience as a well as insights from the pharmaceutical industry. Most recently, the Library Synthesis Core has benefited from a transformative initiative underway in the Broad Institute Chemical Biology (BCB) Platform. During 2007, under the leadership of CMLD P.I. Stuart Schreiber and newly recruited BCB Platform Director, Dr. Mike Foley, the Broad Institute made substantial investments in personnel and equipment to enhance dramatically its capabilities in library synthesis, small-molecule screening, and chemical informatics. The result is a truly integrated platform with increased capacity, improved efficiency, and a continuous informatics environment, allowing seamless passage of compounds from production into screening. Dr. Foley and his team of synthetic chemists have brought a deep understanding of production-level library development and implementation to the CMLD community. During the renewal phase of the Broad CMLD, we will formalize this collaboration by establishing the CMLD Library Synthesis Core under his guidance. The funds allocated to the Library Synthesis Core in the proposed budget will be used to support efforts of the BCB Platform team specifically directed towards production of CMLD compounds. This model will enable the CMLD Center to leverage existing expertise and infrastructure at the Broad Institute towards meeting our goals in testing the suitability of new CMLD methodology for scalability and suitability for library production, as well as our goals in library production. We anticipate that the CMLD Library Synthesis Core will impact the success of Projects throughout the entire renewal phase of the Broad CMLD, with its key activities evolving as projects progress: ? Efforts will initially be directed at the testing of new chemical methodology, especially that arising from our Incubator Project (Project 3) in the context of greater scale and reliability for incorporation into actual library syntheses. ? Efforts will also be directed at collaborating on development activities to ensure sharing of expertise, consideration of practical issues affecting implementation, leveraging of key equipment and supplies, and a smooth transition to the production phase. ? Following development, the library synthesis core will focus on production of pilot libraries based upon innovative CMLD B/C/P pathways. ? Following production, the Core will provide compound management capabilities to format the collection in a platform appropriate for small-molecule screening. Compounds generated in the pilot library with appropriate quantity and purity will be submitted for screening by MLPCN. ? Throughout the process, the Core will provide analytical chemistry and quality control support to all Projects as necessary. Quality control will be performed on an ongoing basis to monitor for decomposition of the small-molecule screening collection. ? Following biological screening, the Core will provide necessary informatics capabilities to support the chemical informatics research activities of Project 4. For example, Dr. demons'objectives in Project 4 will depend on his ability to obtain chemical structures associated with descriptors encoding the individual steps of the synthetic pathway. The Library Synthesis Core will provide these electronic data. These activities will establish strong working relationships between CMLD trainees and BCB Platform professional scientists. These relationships are necessary not only for achieving our immediate aims in the CMLD proposal, but for CMLD chemistry to have a greater impact going forward: if the CMLD efforts prove to be successful and we accomplish a library synthesis of 500 or more members, a likely consequence, beyond the scope of CMLD funding, would be to adapt the underlying chemistry to a library synthesis of 30,000-45,000 members. Large-scale efforts of this type are not envisioned to be part of the CMLD project and instead will be undertaken by the BCB Platform using alternative funding mechanisms, drawing extensively on the expertise of the CMLD Center and its trainees.
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