Biology
Biology

H. Martin Seidel, Ph.D.
Institute Director


Jennifer L. Harris, Ph.D.
Director of Protease Biochemistry


Our drug discovery efforts start by combining the traditional disciplines of molecular biology, cell biology, biochemistry, and molecular and cellular pharmacology with advanced technologies available at GNF, such as our high throughput screening facilities. This provides our drug discovery teams with a thorough understanding of targets and pathways and of the consequences of their modulation. Some of our activities include:

  • Target identification/validation (in collaboration with GNF technology and discovery groups)
  • Assay development
  • Screen miniaturization to 1536-well format
  • High throughput screening
  • Functional and phenotypic assay development
  • Support of lead optimization activities through to clinical candidate identification 


Primary Responsibilities
The biology groups pursuing drug discovery at GNF work along the entire continuum of the drug discovery process.  Their collective goals are: 

  • To identify high quality, chemically-tractable, small molecule leads for targets or pathways of choice that form the basis for full medicinal chemistry optimization or a target identification effort 
  • To develop for each project an array of biochemical and cell-based assays to fully characterize leads and appropriately guide medicinal chemistry SAR efforts with high quality, reproducible data 
  • To work as part of an integrated team with medicinal chemists, in vitro and in vivo ADMET scientists, and in vivo pharmacologists to optimize leads into drug candidates ready for clinical development


In addition to these key activities, drug discovery biologists also play an active role in designing projects that leverage GNF’s strengths in genomics and proteomics to identify and validate novel targets. These projects draw on internal expertise in particular target classes or pathways, academic relationships, and collaborations with Novartis colleagues. For exceptional ideas, biologists may write proposals to obtain GNF funding for postdoctoral positions, which are awarded on the basis of competitive merit.

Lead Discovery Capabilities
GNF drug discovery biologists develop highly optimized and validated assays that are miniaturized into a 1536-well format and run on GNF’s fully automated, ultra-high throughput screening platform. The GNF uHTS system was designed and built in-house and has state-of-the-art screening capabilities, including the ability to run up to a million assay wells per day in standard biochemical and cell-based assay formats. By combining our rapid assay development and uHTS systems, we have the ability to screen up to 30-50 targets/pathways per year against GNF’s diverse library of over 1.7 million compounds. This approach often yields highly active, diverse screening hits that can quickly evolve into candidates for lead optimization.

Lead Optimization Activities
GNF biologists engaged in drug discovery projects develop a thorough understanding of their targets or pathways.  Because of this, the scientists can design a broad spectrum of appropriate biochemical and cellular assays to support lead optimization efforts. These assays provide important information about the potency, efficacy, selectivity, and functional activity of lead compounds. The data derived from such assays are a critical component of the lead optimization process and provide guidance to ongoing medicinal chemistry SAR efforts and further ADMET or disease model testing.

Selected Publications

  • Zhou V, Han SL, Brinker A, Klock H, Caldwell J, Gu XJ. A time-resolved fluorescence resonance energy transfer-based HTS assay and a surface plasmon resonance-based binding assay for heat shock protein 90 inhibitors. Anal Biochem 2004;331(2):349-357.
  • Wang Y, Klock H, Yin H, Wolff K, Bieza K, Niswonger K, Matzen J, Gunderson D, Hale J, Lesley S, et al. Homogeneous high-throughput screening assays for HIV-1 integrase 3beta-processing and strand transfer activities. J Biomol Screen 2005;10(5):456-62.
  • Han S, Zhou V, Pan S, Liu Y, Hornsby M, McMullan D, Klock HE, Haugen J, Lesley SA, Gray N, et al. Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors. Bioorg Med Chem Lett 2005;15(24):5467-73.
  • Epple R, Azimioara M, Russo R, Xie Y, Wang X, Cow C, Wityak J, Karanewsky D, Bursulaya B, Kreusch A, et al. 3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2. Bioorg Med Chem Lett 2006;16(21):5488-92.

     

    Please click here for a full list of group publications