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Jun 1, 2011 (Vol. 31, No. 11)

Kinase Inhibitor Obstacles Falling

Structural Modeling and Improved Assays Propel Advances in Field

  • Click Image To Enlarge +
    Crystallographic studies with tivantinib (ARQ 197, center) in complex with c-Met (bottom left) have revealed intriguing structural information showing how hydrophobic clusters occlude ATP binding in the inactive form of the kinase (top left). Such catalytically incompetent conformations may provide insight into the conserved structural features of kinases in the inactive state. A similar nonpolar environment is shown (right) arising from a different inhibitor co-crystallized with a kinase from the serine/threonine family. ArQule

    Protein kinases drive many critical cellular events including proliferation, metabolism, apoptosis, and differentiation. They catalyze the transfer of the terminal phosphate from ATP to tyrosine, serine, or threonine residues of the kinase itself or another protein substrate. Therapeutic inhibition of protein kinases has revolutionized the treatment of certain cancers.

    New inhibitors are also targeting a host of other conditions from atherosclerosis to neurodegenerative diseases. Although the first FDA-approved drug was an antibody that targets the extracellular domain of the epidermal growth factor receptor (1998, Herceptin®/Genentech), several small molecule kinase inhibitors are now in clinical use with many more in the pipeline. The field continues to experience expansive growth. The global market for kinase inhibitors is expected to reach $20.2 billion by 2014.

    Recent conferences—Informa’s Protein Kinases Congress and GTC’s conference on “Protein Kinases in Drug Discovery”—highlighted new developments in the field that include novel paradigms for drug development, improved inhibitor profiling and selectivity strategies, and expanding targets (e.g., Alzheimer disease and traumatic brain injury).

    Protein kinases have both active and inactive states. While the structure of the active state is well studied across the kinome, this is not the case for the inactive state. Kinases employ diverse mechanisms to control their activation with a variety of structurally different conformations. “These differences may be exploitable for structure-guided drug design,” indicated Mark A. Ashwell, Ph.D., vp of chemistry at ArQule.

    “The current thinking in the field is to develop a new kinase inhibitor paradigm that will combine a better understanding of structure and function and a knowledge-driven design approach. The understanding in the field is growing and it has taken some time to distill, especially how knowledge of the plasticity of kinases can be translated into improved inhibitor design. We are making strides to develop in silico processes for the design of inhibitors that take advantage of changes that take place upon activation.”

    Dr. Ashwell and his team are targeting the inactive state of kinases. “This approach mimics nature’s own mechanism for inhibiting kinase activity and maintains the kinase in a state where it isn’t competing for the abundant ATP.

    “We performed structural and functional studies on inhibitors of the c-Met receptor tyrosine kinase that is implicated in several cancers. We co-crystallized our small molecule inhibitor, tivantinib (ARQ 197), with inactive c-Met and found a conformation that is distinct from published kinase structures. Our structural analysis showed a cleft lined with nonpolar amino acids that were organized into clusters upon ARQ 197 binding.”

    Dr. Ashwell explained that the information they derived from these studies allowed them to generalize to a hypothetical model of other protein kinases.

    “We selected the fibroblast growth factor receptor tyrosine kinase family. Utilizing structural information, we identified inhibitor candidates for optimization in a commercial chemical library. Next, we performed biophysical, biochemical, and cell-based assays as well as x-ray co-crystallography. Our results validated the initial hypothesis that nonconserved hydrophobic residues present in the inactive state participated in nonpolar interactions with these novel inhibitors.

    “We believe that as we are better able to understand the structure and function of kinases, we can successfully exploit a powerful and new chemical space for inhibitor designs.”

  • Neurodegenerative Diseases

    Click Image To Enlarge +
    Cdk5/p25 ribbon and surface representation with a compound from the Laboratory for Drug Discovery in Neurodegeneration at the Harvard NeuroDiscovery Center docked into the model M

    Clinical success for kinase inhibitors has been demonstrated in oncology. However, chronic neurodegenerative diseases (e.g., stroke, Alzheimer disease, multiple sclerosis) represent a large unmet need in the population, said Marcie A. Glicksman, Ph.D., co-director, Laboratory for Drug Discovery in Neurodegeneration (LDDN), Harvard NeuroDiscovery Center.

    “For most neurodegenerative diseases, there is no significant disease-modifying agent available on the market. To develop candidates, one not only faces the typical challenges for developing kinase inhibitors (selectivity, efficacy, etc.), but also other issues. For example, in Alzheimer disease, animal models may not replicate key features of the human disease. Also, potential biomarkers have recently been identified but still have to be correlated to disease.”

  • Analysis & Insights: Protein Kinase Inhibitors for CNS Diseases at the Research and Discovery Phase

    While only one kinase inhibitor targeting neurodegenerative disorders has reached the clinic to date, vast efforts to sift through relevant pathways and identify inhibitors of kinases thought to be involved in these diseases are under way. Get the details here.

  • The LDDN has established a collaborative model for drug discovery that works with academic laboratories in the U.S. and worldwide to create and then license out leads. “We have a library of 150,000 compounds utilized by biologists and chemists who subsequently work on optimizing candidates identified from high-throughput screening. We also have imaging capabilities and the ability to test in animal models.”

    This approach is gaining in popularity, Dr. Glicksman noted. “There is a real need to work on more challenging diseases in academic settings. We can take the time to solve issues and take bigger risks whereas big pharma cannot. Academic institutional research has better opportunities for receiving funding for projects with large translational value. Once academic institutions solve some of these challenging issues, we can then work with big pharma to take the next steps.”

    The NeuroDiscovery Center has developed lead candidates for multiple kinase targets. One target is the erythropoietin-producing hepatocellular carcinoma receptor that is involved in cell-signaling pathways in discrete areas of the brain. All members of the family have an intracellular tyrosine kinase domain. Inhibitors could be used to modulate cerebral ischemia and traumatic brain injury.


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