"Design, Synthesis, and Evaluation of PKC Modulators: a Function Oriented Synthesis Approach"
Bryostatin-1 is a natural product that was originally isolated from the marine sponge Bugula neritina more than 50 years ago. Following its isolation, it has demonstrated unprecedented clinical potential across a number of indications, including HIV/AIDS eradication, the treatment of Alzheimer’s disease and neurological disorders, and cancer immunotherapy. Despite this unique portfolio of indications, Bryostatin-1 is a natural marine product that is neither evolved nor optimized for the treatment of human disease.
Historically, the scarcity of isolated material and the challenges associated with making modifications of the delicate and densely functionalized Bryostatin skeleton have precluded efforts to optimize the biological activity of this natural product lead through derivatization and exploration of structure-activity relationships (SAR) around the macrocycle.
Drawing on the synthetic platform we developed in our lab, we not only accomplished the synthesis of SUW-133, our lead Bryostatin analog, but we also developed analogs and prodrugs of SUW-133 that could allow us to improve the activity and latency reversal capabilities of these drugs. Using a function-oriented synthesis (FOS) strategy informed by a combination of computational and biological data surrounding the Bryostatin scaffold’s interaction with its protein target, protein kinase C (PKC), we synthesized a series of SUW-133 analogs and prodrugs designed to maintain PKC affinity while allowing for a systematic investigation of their biological function. By leveraging the modularity of our SUW133 synthesis, we developed complementary late-stage diversification strategies that provide efficient synthetic access to modifications in the B- ring and on the primary pharmacophoric - OH. In agreement with our pharmacophore model, these new analogs retain affinity for PKC, and the prodrugs were able to increase the half-life of the compound from 24 hours to 7 days, while improving the affinity for the compound in latency reversal assays.
Finally, since Bryostatin-1 and other PKC modulators have been shown to prevent progressive neurodegeneration in a mouse model of multiple sclerosis (MS), we worked on developing a new PKC modulator, TPPB. Optimizing a synthesis for the compound, we were able to bring the known step-count down for the compound and improve the yield, allowing for a scalable way to not only make the compound, but generate close-in analogs of TPPB that could improve upon the binding and efficacy of the compound.