Part I: Visible light photoredox catalysis is a powerful method to modulate small molecule
and transition metal reactivity, but we lack insight into the mechanistic basis of this
technology. I will present a comprehensive study of an industrially important
Nickel/photoredox catalyzed C–N cross-coupling reaction. Using a combination of
reaction kinetic analysis, ultrafast spectroscopy, and stoichiometric organometallic
studies, we elucidate the key steps in the mechanism of this reaction. We then leverage
these insights to design a new photocatalyst yielding improved reaction rate (>30-fold)
and quantum yield (>10-fold).
Part II: Targeted degradation of cell surface proteins can address therapeutic challenges
rooted in pathologic over-expression or over-activation of a disease-driving protein.
Directly introducing cell surface proteins to address therapeutic challenges rooted in
pathologic protein deficiency or dysfunction remains an unsolved challenge. I will present
the development of bispecific molecules (TrogoTACs) capable of inducing contactdependent
protein transfer between cells by redirecting trogocytosis in a targeted fashion.
To accomplish this goal, we designed chimeric antibody-small molecule conjugates with
specificity to cell surface proteins displaying mutually exclusive expression on donor and
acceptor cell types. The protein transfer process is rapid, requires cell-cell contact, and
depends on expression of the receptors targeted by the TrogoTAC. Transferred proteins
can then redirect T cell engager cytotoxicity to rewire therapeutic targeting towards
otherwise unresponsive cancer cells.