Scientists at Scripps Research have developed a synthetic version of the natural compound cepfaugin I, which has shown to be a powerful and promising anticancer agent. Through their development, they were able to understand how the bacterial secretion is able to block proteasome, a strategy found in many existing cancer medications used to destroy cancer cells. Scientists say the bacterial extract cepafungin I is in the same class as several FDA-approved anticancer drugs, with some improved properties.
Their study, “Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I,” is published in Cell Chemical Biology and led by chemists Hans Renata, PhD, and Alexander Adibekian, PhD.
The researchers were first interested in cepafungin I because of its use as an antifungal substance and as a promising anticancer agent. The compound kills cells by acting on the proteasome, which is responsible for clearing away waste produced by cells. To overcome the challenge of studying the compound’s activity or potential as medication due to its complex structure, the researchers sought to create the compound, and were able to in just nine steps.
“The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I toward the β2 and β5 subunits of the proteasome,” the researchers wrote.
The scientists utilized certain enzymes that enabled construction of one of the compound’s key building blocks, an amino acid to speed up the process. Then they developed other creative chemistry methods to simplify construction of other parts of the molecule, which included a branched lipid portion that contributes to the compound’s potent activity. Alexander Amatuni, a graduate student at Scripps Research explained, “Our approach saved us many steps in synthesizing the final compound compared with using classical chemical approaches.”
Once the scientists were done, they observed that in addition to being selective at targeting two sites on the proteasome, the compound didn’t show any unwanted cross-reaction with other proteins in cells, a feature that could make it serve as a better drug candidate.
“Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I,” noted the researchers.
Adibekian, who is also an associate professor of chemistry at Scripps Research, noted three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, that are already approved by the FDA for the treatment of multiple myeloma, but have potential side effects and may develop resistance over time. “There is a need for alternative, more specific proteasome inhibitors.”
Going forward, the scientists plan to continue structure-guided design of similar molecules with alternative structural features in search of useful compounds with superior anticancer activity. “We’re excited about developing the molecule further,” Adibekian declared.