Drug Discovery and Structural Biology Shared Resource ABSTRACT The Drug Discovery and Structural Biology (DDSB) Core collaborates with City of Hope investigators to validate, develop, and optimize novel therapeutics. To accomplish this, the DDSB provides a comprehensive range of services spanning computational methods; high throughput screening (HTS); advanced synthetic methods to produce small molecules, peptides, and challenging oligonucleotides; and structural and biophysical methods. These services provide City of Hope Comprehensive Cancer Center (COHCCC) members with a cohesive platform to rapidly and successfully drive their therapeutic development efforts to meaningful outcomes. All major equipment and instrumentation for the DDSB is located in the Flower building. This includes an extensive array of liquid handling robots; peptide and oligonucleotide synthesizers; multiple incubators and fast protein liquid chromatography (FPLC) systems for protein production and purification; analytical instrumentation to characterize molecular interactions (surface plasmon resonance [SPR], isothermal titration calorimetry [ITC], analytical ultracentrifugation, circular dichroism [CD] with thermal control, etc.); NMR and mass spectrometers for small molecules; and equipment for macromolecular determinations (crystallization and visualization robots and a diffractometer). The DDSB core is co-directed by Drs. David Horne and John Williams, Professors in the Department of Molecular Medicine at the Beckman Research Institute at City of Hope, and supported by highly qualified staff that maintain and operate the equipment while also providing training to COHCCC researchers who wish to operate instruments independently. Oversight is provided by an interdisciplinary faculty Advisory Committee, and user feedback through an annual survey. Since the last competitive renewal, the core contributed to 219 publications by CC members, served 121 unique investigators, 100 (83%) of whom were CC members and represent all five Programs. Of the 100 CC members, 86 had peer-reviewed funding. In addition, since the last competitive renewal, the DDSB has synthesized more than 300 small molecules, 500 peptides, and 950 oligonucleotides (aptamers, GpC-conjugates, etc.). During that same period, over 450 crystallization and optimization trials were conducted, over 250 crystals were screened for diffraction, over 40 novel crystal structures/complexes were determined, and over 300 SPR experiments, 35 in silico screening/molecular dynamics projects, and 23 HTS projects were conducted. The DDSB has also developed synthetic methods and processes leading to full-scale production of complex small molecules under GMP conditions. Efforts stemming from the DDSB have led to 32 technology/patent portfolios involving 76 patents (pending and allowed), four licenses, and a substantial sponsored research agreement (>$1M).

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Subcommittee I - Transistion to Independence (NCI)
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Beckman Research Institute/City of Hope
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Slavin, Thomas P; Banks, Kimberly C; Chudova, Darya et al. (2018) Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing. J Clin Oncol :JCO1800328
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