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November 15, 2009 (Vol. 29, No. 20)

Developments in Focused Kinase Libraries

Research Using Smaller Collections Reported to Shorten Discovery Efforts

  • Binding Modes

    Click Image To Enlarge +
    Figure 2. Ribbon diagram showing the binding of a potent SFK33 compound to the kinase PIM-1

    A library design strategy focusing on alternative ligand-kinase binding modes is largely based on the novel binding modes observed in the cocrystal structure of a potent compound from a SoftFocus library (SFK33), bound to the kinase PIM-1 (Figure 2). In this case, the compound binds to a catalytic lysine residue while  making no contact with the hinge region. This binding mode provides a unique paradigm for novel library design.

    Only those scaffold ideas that pass this in silico docking are progressed to the next stage of evaluation, which includes a novelty check on structures and adherence to key hit/lead physicochemical property checks. Screening such libraries has generated information-rich data, generally consisting of higher hit rates (compared to screening diverse collections of unrelated compounds) together with key structure-activity relationship data that can speed up hit-to-lead programs.

  • Focusing on Success

    By constantly refining the compounds using in silico methods, including those described above and with the development of innovative in silico models and applications such as Cresset BioMolecular’s molecular Field technology, the latest advances in kinase research can be incorporated into novel libraries. Consequently, this may also provide a strong intellectual property position to those who screen them. Indeed, based on the screening of SoftFocus kinase libraries alone, over 70 known patents have been applied for or granted.

    A recent example from Galapagos highlights this. Following a screen of some 16,000 BioFocus focused kinase compounds, three hit series were identified that showed structure-activity relationships against a novel rheumatoid arthritis target. Two of these compound series were progressed to the hit-to-lead phase and subsequently one series was optimized, and a compound is currently undergoing clinical trials. The project time from screening to preclinical candidate nomination was three years.

    There is no doubt that the drug discovery process should be shortened whenever possible. It is essential to improve the lead discovery process. Focused compound libraries such as the SoftFocus collection have the inherent capabilities to provide a robust hit discovery process, with good hit-to-lead conversion rates and shorter development times.

    Furthermore, such libraries can maximize the benefit of new techniques such as in silico modeling, enabling them to be consistently developed over time. BioFocus has also maintained flexibility in its library-generation processes using these techniques, which has enabled the development of novel libraries with proven results.

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