Stephen W. Fesik, Ph.D.
Professor of Biochemistry & Pharmacology & Chemistry
Orrin H. Ingram II Chair in Cancer Research
Tadashi Inagami Chair in Biochemistry
Cancer drug discovery using fragment-based methods and structure-based design
Research Keywords: Drug discovery, cancer, NMR, fragment-based screening, structure-based design, undruggable targets
Research Specialty: Cancer drug discovery using fragment-based methods
Research Description: In the last 30 years, we have learned a lot about cancer. However, it still remains a huge unmet medical need. Some of the most validated targets based on a large number of studies are impossible or difficult to drug such as those involved in protein/protein or protein/DNA interactions. This is due to the lack of suitable pockets for a small molecule to bind to these target proteins.
The Fesik lab uses fragment-based methods to identify small molecules (fragments) that bind to these difficult targets and structure-based design to optimize them for binding to the target protein.
Current projects in the lab include:
- Discovery of KRAS inhibitors
- Discovery of WDR5 inhibitors
- Discovery of MYC/MAX inhibitors
- Discovery of b-catenin degraders that inhibit the WNT pathway
- Discovery of mTOR inhibitors
- Discovery of Mcl-1 inhibitors
- Discovery of novel ligands for E3 ligases
- Development of new NMR methods for fragment screening
The Fesik lab uses a multidisciplinary approach to drug discovery that involves the cloning, expression, labeling, and purification of proteins, NMR-based fragment screening, structure determination using NMR and X-ray crystallography, design and synthesis of small molecules, and conducting biochemical and cell-based assays.
SIGNIFICANCE
The discovery of new drugs that have improved efficacy and less toxicity would help the many patients afflicted with this horrible disease. By targeting the proteins that are the cause of many cancers, these drugs would be used by a large number of patients. The problem is that these targets are thought to be difficult or impossible to drug. Fragment-based methods that Fesik pioneered are ideally suited for discovering inhibitors of these challenging proteins.
Postdoctoral positions available: There are no positions available at this time.