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Nov 1, 2013 (Vol. 33, No. 19)

Interrupting Cell Signaling

  • In light of the cancer therapeutics currently approved that target the ATP binding sites of a handful of kinases, only a handful of these enzymes (about 20% of the kinome) have been exploited therapeutically, noted Dr. Fabbro, who added, “only a limited set of chemical probes is available to functionally annotate the kinome (including the untargeted kinases) and to stimulate new drug discovery efforts to address unmet medical need.”

    A key challenge is to understand the “disease dependence” of a target kinase and to anticipate the potential for resistance following treatment with kinase inhibitors. Resistance can develop through various mechanisms, and minimizing the risk of resistance in the target kinase as well as the reactivation of relevant pathway(s) necessitates the use of a comprehensive combination of inhibitors, explained Dr. Fabbro.

    A variety of tools and techniques are available to probe the kinome and define the functions of a specific kinase. These include the use of small molecule inhibitors, RNA interference (RNAi), and genetic knock-out or knock-in models.

    An additional challenge in kinase-based drug discovery involves targeting kinases for which the cellular-signaling pathways are poorly or not at all understood. Deconvoluting the unknown cellular signaling as well as identifying the pathway in which the target kinase is embedded can be laborious and time-consuming, noted Dr. Fabbro. In essence, the various approaches, which include genetics and phosphoproteomics, are aimed at obtaining the relevant substrates of the known kinase in the unknown pathway.

    Technology advances that could accelerate research on signal-transduction pathways and the identification of selective kinase inhibitors would, for example, “provide a common framework for understanding the activation of the kinase, disease causality, therapeutic modalities, and resistance as well as selectivity,” in Dr. Fabbro’s view. These include structural knowledge of the inhibitor-kinase interaction (x-ray, nuclear magnetic resonance, isothermal titration calorimetry, etc.) as well as pathway analysis combined with genetic and pharmacological tools.

    The ultimate goal is to obtain a comprehensive annotation of kinases with their pathways and the understanding of their involvement in diseases. “The availability of selective chemical probes to functionally annotate the untargeted protein kinases will stimulate new drug discovery efforts to address unmet medical needs,” said Dr. Fabbro. All of these technology gaps will likely require a collaborative effort by a network or consortium of research groups.

  • Designed for Potency

    Dr. Dowling’s presentation highlighted the importance of developing an early understanding of the physical properties of kinase inhibitors that may influence activity endpoints such as mechanistic or phenotypic assay readouts.

    “We identified an early chemical series whose activity in cell-based formats was shown to correlate with the lipophilicity of the compounds,” said Dr. Dowling. “In a situation like this, if the lipophilicity is relatively high and the activity is modest, then further increases in potency are likely to be achieved only with a molecule whose overall drug-like qualities are poor.” Dr. Dowling’s group identified other compound series in which significant gains in potency could be achieved in a property-independent manner “and rationalized through x-ray crystallography of a ligand bound to the target.”

    One of the challenges in identifying a new starting point and novel chemical series against a particular drug target is the limited knowledge of and experience with these new chemical entities. Structure- and property-based design approaches can generate data useful in establishing a profile of a newly discovered chemical series and assessing its drug-like potential. This information can help guide early-stage screening and prove useful to later project teams that may identify hits in subsequent screens using this series.

    “Structure-based approaches offer a visual and conceptual framework for generating novel ideas that can be tested experimentally, initially using in silico methods and then in other settings, such as test tubes, cells, and larger organisms. In an early discovery program, they can be applied to enrich the diversity of your screening output by facilitating the design and evaluation of additional, potentially novel chemical scaffolds,” said Dr. Dowling.

  • Conclusion

    Interest in drug discovery has driven much of the research on the role of protein kinases in a range of signal-transduction processes and in disrupted cell-signaling pathways linked to disease. In turn, this research is contributing to a clearer understanding of the many physiological and biochemical systems in which protein kinases play a role.

    For example, in a study of cytoskeletal signaling, Izabela Michalczyk and colleagues report that a role for protein kinase Cθ is emerging (Journal of Leukocyte Biology 2013). Also, in a genome-wide analysis of kinase-chromatin interactions, Jonathan Göke and colleagues report that the extracellular signal-related kinase ERK2 co-binds to a DNA promoter with a transcription factor that is essential for the pluripotency and self-renewal of human embryonic stem cells (Molecular Cell 2013).

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