San Diego upstart debuts discovery engine that puts a twist to protein degradation
For years, the idea of protein degradation — utilizing the cell’s natural garbage disposal system to mark problematic proteins for destruction — remained an elegant but technically difficult concept. But now established as a promising clinical strategy, with major biopharma players such as Bayer, Gilead and Vertex trying to grab a foothold via partnership deals, a San Diego startup is looking to exploit it and push its limits.
While the frontrunners in the burgeoning space such as Arvinas, Kymera and C4 Therapeutics focus on linking the target protein with an E3 ligase — with drugs that bind to both — Plexium wants to tinker with just the ubiquitin.
“What we are suggesting is completely different. Most of the targets we’re going after do not have any known binders at all. What we’re suggesting is we simply bind to the E3 ligase, and we modify the E3 ligase surface, and see if any one of those compounds that bind to the E3 ligase modifies the E3 ligase interaction sufficiently to redirect it to the targets of interest,” CEO Swamy Vijayan told Endpoints News. “To do what we do, you need the scale.”
The scale derives from the platform developed Vijayan, who has a background in diagnostics and instrumentation. It builds on DNA encoded libraries — a popular screening tool — and integrates cell-based assays to allow for deeper exploration of the tests. Dropping the DNA-tagged compounds into minuscule “pico wells,” he is then able to run tests in nanoliter volumes.
It is essentially an entire drug discovery infrastructure in a benchtop device, he said, with the potential to identify drugs that hit multiple targets through phenotypic analysis.
“For us to do, say, a 100,000-member library assay takes us 15 to 20 microlitres of reagent, whereas for traditional screening that would be a few litre of reagents and planning ahead of time to scale them up,” he said.
After propping up the operation in 2018, Plexium said this funding will allow them to take an experimental compound through IND enabling studies, plotting a quick flip to the clinic to treat solid tumors. With $28 million in new financing, it will also lay the groundwork on some neurodegenerative diseases programs and hunt other potential uses of its platform.
The Column Group and DCVC Bio led the Series A and will send their managing partners, Kiersten Stead and Tim Kutzkey, on the board. M Ventures, CRV and Neotribe Ventures are also part of the syndicate.
“Plexium is an interesting amalgam of cutting-edge engineering coupled with the latest advances in chemistry and biology,” Kutzkey said in a statement.
The approach turns rational drug design on its head, Vijayan admitted, as the process is akin to testing multiple tooltips on multiple screwdrivers to see what works. But it doesn’t mean they are throwing drug development expertise out the window. Earlier this year he recruited John Boylan from Celgene to be CSO, and many on Plexium’s team of 42 are seasoned pharma staffers.
“It’s been a fantastic cross-pollination of ideas,” Vijayan said. “In engineering and diagnostics we’re used to more agile methodologies and certain product development principles and ideas that are very alien to pharma because they put the blinders on, keep going on a very fixed path, a day at a time. [Applying adaptive methodologies at Plexium] is paying a lot of dividends.”