Trainee Spotlight: Nan Bai

• Nan Bai
  PhD Candidate
  Dr. John Karanicolas laboratory
  Fox Chase Cancer Center and University of Kansas

  Biography

  The first step of my scientific career began when I was an undergraduate at Peking University in Beijing where I majored in the life sciences. During my studies, I found that I loved learning about microbiology, genetics, and biochemistry and enjoyed the hands-on opportunities to explore these interests in a research lab.  From these experiences, I considered a future career in microbiology or genetics and made plans to devote myself to studying science. With this original goal, I joined a lab focused on bio-desulfurization of fossil fuels using bacteria. Although I really enjoyed my project, a health scare in my family turned my focus toward medical research. When I was twenty-five years old, my beloved grandfather fell ill with cerebrovascular disease. I remember feeling powerless because there was not much I could do to help, to fix his disease or to make him feel less pain. I thereafter changed my future career plan to devote myself to studying new and more effective ways to treat disease. In 2015, I joined Dr. John Karanicolas’ lab as a graduate student with the goal of studying small molecule drug design. In our lab, we use computational tools to study how drugs bind their targets; a greater understanding of drug-target interactions may lead to the development of more effective drugs. Upon completion of my PhD study, I plan to use this training in the next step of my career in drug discovery at a pharmaceutical company.

  Research overview

  Small molecules that disrupt activity through direct binding to the active site of a targetare effective inhibitors for target proteins with well-defined binding pockets. However, not all proteins can be targeted using the traditional small molecule inhibitor approach.

  PROteolysis TArgeting Chimera (PROTAC) is a new category of inhibitor capable of targeting a wider range of proteins. Effective PROTACs simultaneously bind target molecules and E3 ligases, which leads to the specific degradation of the targeted protein. Compared with traditional small molecule inhibitors, PROTACs are not limited to binding to an active site to induce degradation; instead, they can induce degradation no matter where they bind on the target protein.

  Although several effective PROTAC molecules have been described, the process for designing new PROTACs is lengthy and ineffective. Typically, hundreds of candidate PROTACS are produced and tested; ; ultimately, only the single most effective PROTAC is selected.  This process is both time consuming and expensive.  The focus of my research is to develop a computational approach to rationally design PROTACs. By applying computational tools, we model the interaction between the candidate PROTAC molecule, disease protein, and the E3 ligase.  Once modeled, we then predict the ability of the candidate PROTAC molecule to induce degradation of the target protein. Ultimately, only those candidates with highest activity would need to be synthesized and tested.  To test our computational approach, we applied our approach to published examples of PROTAC molecules, compared our predictions with published cellular data, and found that our predictions matched the published data. Thus, this work demonstrates that our computational approach could provide a reasonable prediction of the activity of a given PROTAC molecule. Taken together, our computation approach and in silico modeling of the PROTAC, target protein, and E3 ligase has the potential to generate more effective PROTACs in a shorter time and for far less money than traditional approaches.

  Featured publication

  Bai, Nan, Heinrich Roder, Alex Dickson, and John Karanicolas. "Isothermal Analysis of ThermoFluor Data can readily provide Quantitative Binding Affinities." Scientific reports 9, no. 1 (2019): 2650.