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.