GRB2 (Human Growth Factor Receptor Bound Protein 2) is an adaptor protein whose overexpression has been linked to CML (chronic myeloid leukemia). Importantly, GRB2 binds its partners through its SH2 (Src Homology 2) domain and acts as a homodimer. Thus, to enhance GRB2 inhibition, we’ve set out to link two known monomeric binders of the GRB2 SH2 domain to yield novel dimeric antagonists. These synthesized dimeric antagonists are designed to mimic endogenous phosphotyrosine binding residues and simultaneously bind dual GRB2 SH2 domains, thus blocking the activity of the GRB2 homodimer. This method of GRB2 inhibition has not yet been studied despite the significant potential for increased binding affinity of the antagonists and subsequent enhanced biological activity. The motivation, design, and novel synthesis of our dimeric antagonists will be presented, along with a preliminary evaluation of biological activity.

Synthesis of a known binder of the GRB2 SH2 domain from naphthaldehyde

253rd National Meeting (2017)

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