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. 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 derivative that selectively binds the GRB7 SH2 domain. To further improve the efficacy of this lead molecule, we used rational design to develop a new library of GRB7 inhibitors. Progress was made in optimizing an efficient synthesis to build the core scaffold for the GRB7 inhibitors via a novel domino cyclization reaction. It was determined that this cyclization is best promoted under S<sub>RN</sub>1 (unimolecular radical-nucleophilic aromatic substitution) conditions; this approach yielded a library of compounds with a unique furoquinoxaline core and varied substitution. The development of the library of GRB7 inhibitors and the optimization of this novel cyclization reaction will be presented.

Development of a novel synthesis for inhibitors of GRB7

251st National Meeting (2016)

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