Chemical & Structural Biology (CSB)
Two broad areas tie the chemical-structural and cancer biology communities together. First, structure-based drug design and biophysical characterization of drug inhibition. Several structural biology laboratories have successfully developed biophysical and structure-based drug design projects for new cancer treatments and diagnostics. Therefore the infrastructure and know-how are in place to successfully apply this expertise to additional cancer related problems. The second broad area is the use of chemical tools and principals to study biological problems, an approach called Chemical Biology. The basic approach applies synthetic and medicinal chemistry principals and methods to design novel molecules that probe cellular function. In the CSB program, such capabilities are used to create new molecules targeting tumor-associated pathways. CSB provides the leadership and guidance required to promote the application of structural-chemical expertise to cancer research. To achieve these broad goals, CSB leadership focuses on the following three specific aims.
1. Make modern tools of structural biology available to cancer related projects – Since 2008, structural biology has substantially grown at UC Irvine and now has 2 NMR, 4 crystallography, and 3 computational biology groups which are all highly interactive. In addition, UC Irvine is recruiting distinguished scientists to lead new initiatives, and has made a major commitment of resources to develop a center in transmission electron microscopy (TEM). Towards that effort, Chemical Engineering has successfully recruited Prof. Xiaoqing Pan, a world renowned leader in materials science and an expert in TEM. As a continuation of this initiative, CSB leadership is working to recruit additional structural biologists who use cryoelectron microscopy to define structures of large molecular complexes. This institutional investment provides a substantial addition to the arsenal of structural biology tools available to CFCCC members. Program leaders will therefore work to expand CSB membership to include these newly recruited faculty and will work to make these cutting edge technologies accessible to CFCCC members by brokering inter-programmatic partnerships.
2. More broadly incorporate synthetic chemistry into cancer related projects – UC Irvine is world renowned in synthetic organic chemistry and with the major changes in CSB beginning in 2009 there was a significant increase in collaborative interactions between chemists and biologists. A majority of these highly successful collaborations involve structure-based drug and inhibitor design ultimately leading to compounds targeted to specific enzymes and proteins. Several of these projects are advancing to stages of toxicity tests in animal model studies. Program leaders aim to maintain this momentum towards the clinic by facilitating application in a clinical trials setting. CSB also aims to more broadly extend the use of chemical tools to probe the state of living cells. This approach, often called bioorthogonal chemistry, enables the interrogation of macromolecules in living cells without disrupting cellular functions, thus enabling important insights into the differences between normal and cancer cells. Given the promise of this approach, and in coordination with the CFCCC leadership, new chemical biology faculty have been hired with expertise in bioorthogonal chemistry (Spitale, Ziwy, Zhao). CSB leadership will work to integrate these new members into intra- and inter-programmatic collaborations within the cancer center.
3. Promote collaborations – There is a natural connection between structural and chemical biologists, and several successful intra-programmatic collaborations have been established amongst the CSB membership. However, bringing together the chemical-structural biology community with members of the OIB, SPT and CPOS programs will benefit from a “molecular matchmaking” service, a service that actively connects biologists with ideas for promising molecules and chemists with the synthetic abilities to make those molecules. “Matchmaking” has been one of the most important activities developed by the CSB leadership. Through workshops and symposia, the two communities have been brought together to first, learn about each other’s work and second, promote collaborations. CSB leadership will expand this mechanism to actively encourage new collaborations and to provide technical support in the way of synthetic chemistry and sample preparation for NMR spectroscopy and crystallography. Several of the projects summarized here are the direct result of these efforts.
|Tom Poulos, Ph.D.||Gregory Weiss, Ph.D.|