Synthesis and Evaluation of Novel RSK Inhibitors in a Living Human Breast Model

RSK p90 Ribosomal S6 kinase is critical for breast cancer proliferation and thus a promising target for therapeutic intervention. A highly specific inhibitor of RSK, called SL0101, was previously discovered but found to possess poor biological stability and potency. The purpose of this project is to identify a drug for breast cancer based on SL0101 that works by inhibiting RSK, by designing and chemically synthesizing analogues of SL0101 that improve on its biological stability and potency and ultimately evaluating them in a living human breast tissue model for anticancer activity. The major findings in this year of funding are the discovery of analogues that are more biologically stable than SL0101 but retain its anticancer activity, the solution of an X-Ray crystal structure of SL0101 in complex with RSK2, and the use of this crystal structure in the discovery of an analogue that in preliminary experiments demonstrates improved potency over SL0101. These discoveries represent significant steps toward the goal of identifying an analogue of SL0101 that could be used as a drug for breast cancer.