PROJECT SUMMARY
14-3-3 proteins are at the crossroads of diverse cellular processes relevant to cancer, such as signal
transduction, cell cycle progression and apoptosis. This family of hub proteins regulates these functions through
an expansive network of protein-protein interactions (PPIs) that constitute the 14-3-3 “interactome.” Small
molecule modulation of the 14-3-3 interactome is therefore of significant interest for cancer treatment, especially
given the role of 14-3-3 proteins in resistance to standard of care drugs. Drugging the 14-3-3 signaling hub also
enables multiple cancer-relevant processes to be perturbed in concert. Although modulation of 14-3-3 PPIs
remains underdeveloped, the natural product cotylenin A presents a molecular platform to address this
deficiency. Cotylenin A stabilizes 14-3-3/partner interactions by functioning as a rare “molecular glue.” This is
believed to underlie cotylenin A’s notable anticancer activity and ability to sensitize cancer cells to existing
treatments while sparing normal cells. Additionally, cotylenin A’s uncommon binding mode carries advantages
of improved drug selectivity and lower affinities required for efficacy. However, cotylenin A has not been
developed as a therapeutic due to loss of natural sources and lack of efficient and readily diversifiable syntheses.
This proposal seeks to invigorate the development of cotylenin-based cancer therapies through chemical
synthesis. Leveraging our group’s expertise in organic synthesis, we will develop an efficient and modular route
to cotylenin A. Proof of concept for this synthetic strategy to access the cotylenin core has already been
established, and will facilitate completion of the cotylenin A synthesis. The cotylenin core will enable immediate
diversification at several positions to generate analogues based on existing crystallographic data. Modification
of the synthesis at early stages will also allow structure-based diversification at additional sites, including one
that provides a novel means to achieve specificity in PPI modulation. The anticancer activity of the analogues
will be evaluated to elucidate structure-activity relationships. We will also conduct proteomic studies to identify
the affected protein targets. This knowledge will guide iterative medicinal chemistry optimization of cotylenins.
Research will be carried out at Scripps Research, an institution that excels in synthetic chemistry and chemical
biology, and fosters strong collaboration across the two fields. I will receive training in complex molecule
synthesis from Prof. Ryan Shenvi, a leader in the field, as well as training in chemical biology by performing
biological and proteomic studies in collaboration with Prof. Chris Parker at Scripps Research. This work is
complimentary to my doctoral training in the study of organometallic reaction mechanisms.