Sanford-Burnham Medical Research Center - National Cancer Institute

anford-Burnham Medical Research Institute is one of seven NCI-designated basic research Cancer Centers. The Institute is among the world leaders in areas of fundamental interest to anti-cancer drug discovery, including studies focusing on mechanisms of cell survival and cell death, cell motility, invasion and angiogenesis, cell stress and intracellular signaling. Most notably, dedication at Sanford-Burnham to apoptosis and cell death research has translated into a wealth of domain-specific expertise and an abundance of unique reagents that has enabled novel bioassays for high-throughput chemical library screening (HTS). In 2005, Sanford-Burnham created the Conrad Prebys Center for Chemical Genomics (CPCCG), which is dedicated to the advancement of knowledge in disease-relevant chemical biology and the improvement of human health through the targeted application of state-of-the-art small molecule screening and drug discovery technologies. The CPCCG participated in the pilot phase of the Molecular Libraries Screening Centers Network (MLSCN) within the NIH Roadmap Initiative in 2005-2008, and is currently one of four Comprehensive Centers in the production phase of the Molecular Libraries Probe Production Centers Network (MLPCN). Out of these efforts, over 125 HTS campaigns have been conducted, leading to the generation of 55 probes against novel targets, 46 probes representing new chemical scaffolds, over 60 scientific publications and numerous patent applications.

Sanford-Burnham's infrastructure for chemical biology and drug discovery resides in 10 core facilities staffed by skilled professionals with extensive pharmaceutical industry experience that encompasses the breadth of HTS assay development, chemical library screening, cheminformatics, medicinal chemistry, hit-to-lead optimization and project management disciplines. The 10 core facilities include:

Protein Expression Core, which utilizes bacteria or insect systems for large-scale protein production and chromatographic purification of multi-milligram quantities of proteins for use in screening assays or for structure determination.

Assay Development Core, which provides expertise and instrumentation to create and optimize high-throughput (HT) assays in a variety of formats (96, 384, 1536 well) and using the full diversity of assay technologies, including biochemical, cell-based, and high content screening (HCS) assays based on multi-spectral cell imaging.

Chemical Library Screening & Compound Library Management Core, which provides access to an in-house ~325,000 compound library, unique natural product libraries, coupled with several fully integrated, robotic liquid handling systems for HTS and ultra-HTS in 96, 384, or 1536 well formats, representing a throughput of nearly 500,000 compounds per day at Sanford-Burnham's San Diego site and with uHTS capabilities of over 2.2 million compounds per day at the Institute's Orlando, Florida site. The platform accommodates all types of biochemical, traditional cell-based, and multi-spectral high content screening (HCS) assays using high-throughput microscopy (HTM)-based cell image analysis.

In Silico Screening/Computational 3D-Modeling Core, which utilizes a dedicated Linux cluster, and applies docking algorithms for screening a virtual library of >1 million compounds for hits against protein targets when a 3D-structure is available.

NMR capabilities include a dedicated 700 MHz, two 600 MHz, and a 500 MHz instruments equipped with automatic sample changers and cryogenic probes for studying interactions of chemical compounds with protein or nucleic acid targets (hit validation), along with a ~4,500 chemical scaffold library for fragment-based screens in de novo hit identification and optimizations projects. The instruments can also be used for compounds' structure elucidation while additional lower field instruments are available for compound structure confirmation and quality control.

X-Ray Crystallography Core, which provides robotic protein crystallization capabilities and x-ray diffractometers for determination of protein/chemical compound complexes at atomic resolution.

Medicinal Chemistry Core, which performs synthesis and purification of small molecules using a broad range of medicinal, combinatorial, and automated microfluidics-based chemistry approaches, encompassing 18 dedicated chemical fume hoods as well as automated compound purification systems.

Data Management & Cheminformatics Core, which includes relational databases, supporting software, and technical support for cheminformatics applications, with on-line access to an inventory of >8 million commercially available compounds for structure-based searches for identifying readily available analogs of hits, as well as specialized software tools designed specifically to support natural products drug discovery.

Exploratory Pharmacology Core, providing in silico ADME/Tox prediction, analytical pharmacokinetics (PK) and in vitro ADME/T analysis and profiling, and Rapid Assessment of Compound Exposure (RACE) and comprehensive in vivo rodent PK.

Functional Genomics Core, which performs high-throughput screening with a genomewide siRNA library that currently covers ~18k human genes at 4-fold degeneracy (~72k siRNAs) plus several focused libraries addressing classes of targets, such as the druggable genes, ubiquitin-ligases, kinases, GPCRs, proteases, and microRNAs (miRs) on a genome-wide basis. The core has developed a lentiviral cDNA library for gain-of-function screens in partnership with a leading reagent supply company. Additionally, a viral vectors core packages shRNA and cDNA vectors as infectious lentivirus for target validation.

Sanford-Burnham's scientific expertise in cancer biology is validated by our 30 consecutive years as an NCI-designated basic research cancer center. By leveraging this expertise with the drug discovery infrastructure established at the CPCCG, the Institute is poised to contribute to the NCI-CBC and bridge the gap between basic scientific investigation and innovative cancer therapies.