The over-expression of the Grb7 protein (human growth factor receptor bound protein 7) has been linked to various cancers including breast, ovarian, blood, and pancreatic. Grb7 elicits its function solely through protein-protein interactions (PPIs); inhibition of PPIs is a therapeutic modality that the pharmaceutical industry typically does not pursue. This novel approach requires drugs to bind to large surface areas as opposed to much smaller catalytic pockets, often rendering potential candidates too large and non-polar to ever make it to market. Excitingly, Grb7 inhibition was shown to decrease the viability of several breast cancer cell lines, reduce cell migration in pancreatic cancer cells, and delay the onset of tumors in nude mice. This established connection between abnormal Grb7 activity and cancer has rendered the protein a viable therapeutic target. Grb7 functions as an adaptor protein by binding its partners via its SH2 domain (Src homology 2); small molecules that bind the Grb7 SH2 domain have the potential to modulate protein function by rendering the protein ineffective in binding its signaling partners. To that end, previous studies have identified a benzopyrazine small molecule, which selectively binds the Grb7 SH2 domain. To further improve the efficacy of this lead molecule, we used rational design and recent advances in synthetic chemistry to develop new potential drugs. These compounds utilize a cyclized core with varied substitution to enhance binding interactions between the small molecule and the Grb7 SH2 domain. The motivation, design and innovative synthesis of these Grb7 inhibitors along with preliminary efficacy data will be presented.

Investigating Grb7 inhibition by use of small molecules

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.