Royer Lab Student Rotations

Design and synthesis of inhibitors to the cancer target CtBP

The co-transcriptional factor C-terminal Binding Protein (CtBP) has been shown to be up- regulated in a broad range of cancers where it promotes growth and metastasis and inhibits apoptosis. The Royer lab is using structure-based design approaches to develop inhibitors to CtBP that would be useful both as research tools to investigate the role of CtBP in cancer and potentially as lead compounds for antineoplastic therapeutics. Our strongest inhibitor to date was designed to bind in the active site identified in our crystal structures of CtBP (see below). We are using this compound as a scaffold onto which to add additional moieties that may both enhance affinity and biological response. In this project, we use computational modeling software with our CtBP crystal structures to design inhibitors and then synthesize the compounds working with our collaborating medicinal chemist Dr. Akbar Ali. Such compounds will then be tested for binding affinity and, if they bind tightly, used in protein crystallography to delineate precise details of their binding. Favorable compounds identified in this way will then be used by our collaborators to investigate their cellular effects. A laboratory rotation on this project will provide the student with experience in structural biology, computational modeling and/or organic synthesis.

Binding of HIPP (cyan) in the active site of CtBP1 as revealed by the co-crystal structure (Hilbert et al. ACS Chem. Biol. 2015 10, 1118- 1127). This compound was designed based on our previous crystal structures and binds with a dissociation constant of 370nM, the highest affinity CtBP inhibitor discovered to date. The structure shown suggests that adding moieties to HIPP could provide additional favorable interactions for binding.