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Jun 15, 2013 (Vol. 33, No. 12)

Macrocycles Shake Up Small Molecules

  • Insights from Parasites

    In the field of chromatin biology, small molecules have also played an integral part in assessing a cell’s activities.

    Cheryl Arrowsmith, Ph.D., professor of medical biophysics and Canada Research Chair in Structural Genomics, University of Toronto, and members of her lab partake in the Structural Genomics Consortium (SGC), which focuses on large-scale cloning and characterization of human proteins and proteins from human parasites.

    “We are trying to fill in the information that could not be provided by genomics analysis and by using a multidisciplinary approach, we have processed a large number of small molecules, as well as determined the activity of each compound in a biological context,” Dr. Arrowsmith said.

    Her group has employed various techniques in structural biology to determine the 3D structures of proteins, as well as other screening and biophysical methods such as enzyme assays, fluorescence polarization, isothermal titration calorimetry, NMR spectroscopy, and thermal stability, to monitor interactions between proteins, peptides, and small molecules.

    “Our current focus is on chromatin biology, attempting to uncover epigenetic mechanisms that influence basic biological phenomena that may be relevant to cancer therapy, inflammation, and neurobiology. In collaboration with pharmaceutical companies, we are developing unique small molecules—chemical probes—that selectively and potently inhibit specific chromatin regulatory proteins,” she explained. “A unique aspect of this project is that we, and our pharma and academic partners, make these chemical probes freely available for other scientists and researchers to study and better understand the relationship between biology and disease.”

    In a recent publication in Nature Chemical Biology, Dr. Arrowsmith and her collaborators at the University of North Carolina described UNC1215, which is a potent, selective, cell-active small molecule that disrupts protein-protein interactions, a type of protein activity that has traditionally been considered difficult to drug.

    “This chemical probe binds within a conserved protein pocket that normally binds methylated lysine groups (a common epigenetic chromatin posttranslational modification) resulting in the regulation of a specific protein (L3MBTL3) associated with brain tumors. UNC1215 thus prevents the interaction of methyllysine-modified proteins, such as histones, that regulate gene expression,” she said.

    The SGC has also participated in other research studies involving the characterization of small molecules such as JQ-1, an antagonist of BET bromodomains, protein interaction modules that recognize acetylated lysine on histones, and important new drug targets in cancer and inflammation.

  • Click Image To Enlarge +
    University of PIttsburgh researchers have been looking for inhibitors against the cytoplasmic tyrosine kinase encoded by the c-Fes proto-oncogene.

    Kinase inhibitors have also seen extensive efforts in biological and chemical characterization. While this field has exploded over the past decade, many kinase targets remain unexplored in terms of inhibitor discovery. One example is the cytoplasmic tyrosine kinase encoded by the c-Fes proto-oncogene, which is a research focus of Tom Smithgall, Ph.D., professor of biochemistry and chairman, microbiology and molecular genetics, University of Pittsburgh School of Medicine.

    “Together with Src and Abl, Fes was one of the first tyrosine kinases discovered many years ago. However, no inhibitors had been reported for this kinase despite its association with acute myeloid leukemia, multiple myeloma, and other forms of cancer,” Dr. Smithgall explained.

    With his departmental colleague Sabine Hellwig, Ph.D., and collaborators Nathanael Gray, Ph.D., at Harvard Medical School, and SGC member Stefan Knapp, Ph.D., from the University of Oxford, Dr. Smithgall screened a small, kinase-based library of approximately 600 chemical compounds for inhibitory activity against the c-Fes kinase and identified eight classes of inhibitors with significant biological actions.

    “From only 600 compounds, we found 20 to 30 compounds that showed potent activity against c-Fes in vitro and eventually ended up with about five compounds that helped us answer new biological questions about Fes,” Dr. Hellwig said. “Unexpectedly, we found a role for Fes activity in osteoclast differentiation from macrophages, suggesting possible roles for Fes in the osteolytic bone disease associated with multiple myeloma.”

    She added that the team is currently using these inhibitors to look into the role of c-Fes in multiple myeloma and other blood cancers.

    “It is possible that by utilizing this handful of small molecules against c-Fes, we might find additional roles and activities for c-Fes,” Dr. Hellwig said. She and Dr. Smithgall are now working with their collaborators to design second-generation compounds with even greater selectivity and potency against c-Fes.


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