Fragment-based drug discovery (FBDD) is proving to be a successful method for designing drugs. The process involves screening small fragments no larger than 300 Daltons, identifying weak binders, and optimizing the hits via linking or growing. A current shortcoming with FBDD lies in the design of the fragment libraries, which typically consist of compounds that are planar and aromatic. It is possible that using fragments with more three-dimensional structure may provide unique binders of challenging protein targets previously considered to be “undruggable,” such as transcription factors and phosphatases. To validate this hypothesis, transcription factor NFκB1 (p50) was screened against a three-dimensional fragment library developed via diversity-oriented synthesis (DOS) using a fluorescence-based thermal shift assay. Three classes of compounds were found: 1) compounds that stabilize p50, 2) compounds that destabilize p50 and 3) a compound that may cause p50 to dimerize. Hits from the screen will be compared and further validated via different types of biophysical assays. Analogues of the confirmed binders will be synthesized to provide structure-activity relationship information for each fragment and to improve fragment potency. Moving forward, other types of protein targets in addition to NFκB1 will be tested to evaluate the hypothesis of using three-dimensional fragments in drug discovery.
PROJECT: Validation of Diverse Fragments as Binders to NFκB1 (p50)
There are so many reasons why I loved conducting research at the Broad, but maybe the biggest was the collaborative atmosphere. When a difficult problem in genomics or medicine arises, Broad scientists don’t ask themselves how they can succeed individually. They seek out their colleagues for pieces to the puzzle, because they know one person cannot tackle the problem alone. That atmosphere also defined the SRPG experience. It was not uncommon for a student in the Cancer Program to give valuable feedback to a student in the Chemical Biology Program, and vice versa. We worked together as a community to produce something greater than we had imagined.