Abstract
Scientists have come up with an efficient, scalable way to chemically synthesize bryostatin 1, a marine-derived natural PKC modulator that has been in scarce supply, impeding a thorough evaluation of its therapeutic potential.
A team of chemists at Stanford University in California has devised an efficient, scalable way to synthesize bryostatin 1, a natural compound long thought to have some anticancer potential but never fully explored, largely due to its limited availability (Science 2017;358:218–33).
Bryostatin 1 modulates PKC and is produced in low, variable amounts by Bugula neritina, a tufted marine organism typically found in the Gulf of Mexico and other warmer seas. During the late 1980s, the NCI spearheaded a massive effort to harvest this bryozoan, with scuba divers collecting 14 tons—the approximate weight of three African elephants—in total. A mere 18 grams (0.00014% yield) of bryostatin 1 was extracted, which “wouldn't even partially fill a saltshaker,” says Paul Wender, PhD, who led the Stanford study.
This scant stock then supplied clinical trials evaluating bryostatin 1 as a chemotherapy, mainly in hematologic malignancies. John Beutler, PhD, an associate scientist with the NCI's molecular targets program, observes that paclitaxel was developed around the same time; interest in these two natural products was high, he says, because their mechanisms of action were known. By contrast, “we had no clue, at the time, how a lot of other [anticancer] compounds actually worked.”
Unlike paclitaxel, bryostatin 1 “just didn't do much in the trials that were run,” notes Beutler, who was part of the original extraction team. “So it kind of vanished from sight and only resurfaced a few years ago,” albeit as a possible first-in-class HIV latency-reversing agent that might help eradicate AIDS.
Wender thinks bryostatin 1′s scarcity has impeded a thorough investigation of its potential in cancer. “If you don't have enough of the material, you can't figure out how to best use it, or whether modifications would prove more effective,” he points out. The synthetic route designed by his team should address this long-standing supply problem, he says.
Only one other chemical synthesis of bryostatin 1, requiring 57 steps, has been reported. Wender's method is considerably shorter—it takes 29 steps, and the overall yield is 4.8%. “We started with a blank sheet of paper and visualized slicing this very complex molecule in two,” he explains. “One group in my lab was tasked with synthesizing one half, while a different group worked in parallel to make the other half; we then ‘stitched’ both pieces together. It's quite a creative approach overall, I think, that hasn't been done before.”
In terms of a strategy that can be commercialized, “this is getting pretty darn close, looking at the step count and yield,” Beutler says. Wender's work “really points to the usefulness of synthetic chemistry,” he adds, and “should stimulate the conversation around natural products—which tend to go in and out of fashion—in a good way.”
Further trials should shift from assessing bryostatin 1′s cytotoxic capabilities to examining the compound as an immunomodulatory agent. Wender suggests that it may render cancer cells more “antigenically visible” to the immune system, thereby stimulating antitumor immunity. “That's the main possibility we're excited about, at least preclinically,” he says.
Importantly, Wender adds, his synthetic strategy is highly versatile, enabling a wide range of bryostatin 1 analogs to be derived en route. His team produced the first such “bryolog” in 1998 through computer modeling, but “because we now have ready access to quantities of bryostatin 1, we can focus on making and functionally characterizing ‘close-in’ analogs that are exceedingly similar to the parent compound,” he says. These may well be better drugs, he thinks—bryostatin 1 itself has broad affinity for PKC's myriad isoforms, not all of which are therapeutically relevant, but some bryologs are more isoform-selective.
“If FDA approval is achieved, most likely it'll be a bryolog that gets there,” Beutler agrees. “Scalable synthesis, which this study has made feasible, will be absolutely critical for carefully exploring individual [bryostatin 1] derivatives and determining their potential.” –Alissa Poh
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