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.