Drugging the Undruggable: A Talk with Plexium’s Swamy Vijayan

Approximately only 2% of proteins associated with disease are considered to be druggable for small molecule drugs. That is to say, there are known “pockets” that the small molecules can attach to that influence their behavior. On the other hand, researchers note that almost all proteins, including the 98% that are considered undruggable, are modifiable by other proteins.

On October 17, San Diego-based Plexium launched with $28 million in Series A financing. The round was led by DCVC Bio and The Column Group, with participation from M Ventures, CRV, and Neotribe Ventures.

Plexium is focused on developing therapeutics that influence E3 ligases that can degrade proteins, even the undruggable ones. The company’s founder and chief executive officer Kandaswamy “Swamy” Vijayan, took time out to speak with BioSpace about the company and its technology platform, DELPHe.

“The question,” Vijayan says, “is if you somehow hijack the E3 ligases given that they interact pretty much with every protein, could we indirectly modulate the other proteins that are hard to drug. So at its most basic, what Plexium is doing is binding molecules to E3 ligases to see if we can alter their interaction surfaces enough so they go and degrade or modulate the targets we’re interested in.”

The approach is not unprecedented. Celgene Corp. has several drugs that interact with E3 ligases. What makes Plexium’s approach different is DELPHe, which melds biochemistry and biology with engineering and machine learning. The key to it is miniaturization. Many companies utilize microwell plates with dozens or hundreds of wells that contain molecules. They then either manually or robotically insert other molecules into those wells and look for interactions.

DELPHe utilizes literally millions of wells, called picowells, and non-mechanical interactions. The picowells have a single bead coated with a given molecule and associated DNA tag in each well. Small molecules are able to be released from the bead in a controlled dose.

“We make the picowells ourselves and we manufacture these areas of very, very tiny wells, many wells per plate. We make compounds on these using DNA compound libraries, but on solid phase, so the compounds are synthesized on the beads and the DNA molecules are also on the bead. Thereby the DNA encodes the compound that is on the bead,” Vijayan says.

Ultraviolet light, he says, “triggers the compound to release off the bead, so the beads serve as a vehicle to deliver these compounds in these tiny volumes. Rather than pipette it in, we just drop the bead and one bead per well. Once you get the bead in, you add any assay material—we specialize in cell-based, but you could add enzymes or any other type of compound you could think of—in a smaller plate. Then you can analyze how the compound works in your assay.”

Some of the advantages are low cost, the DNA tag is on the bead, not small molecule, so it doesn’t interfere with the assay or create artifacts and is flexible for a variety of different types of assays.

The company was founded in May 2018 and most of the time since was spent on engineering the platform. In the last few months it has moved into drug development. It currently has two compounds in the hit-to-lead stage that they need to optimize. Most of its molecules are in the oncology space, especially solid tumors, with one for a central nervous system indication.

“We’re trying to take one asset through IND-enabled studies and get it close to the clinic,” Vijayan says. “Then we will get a couple more assets right behind it and at the same time scale-up the platform for high-throughput.” They expect lead optimization for the first asset in the next couple months.

He also points out that, “Our platform is revealing so much insight about biology and chemistry that we may consider partnering with other large pharma companies along the way.”

As part of the financing, Kiersten Stead, managing partner of DCV Bio and Tim Kutzkey, managing partner of The Column Group, have joined Plexium’s board of directors.

“Plexium is an interesting amalgam of cutting-edge engineering coupled with the latest advances in chemistry and biology,” Kutzkey said in a statement. “We are impressed with the vision of the DELPHe platform and its applicability to E3 ligase modulation. We believe tuning E3 ligases opens up immense opportunities for first-in-class therapeutics, and we are excited to be supporting the novel approaches and therapeutic opportunities being pursued at Plexium.”

Vijayan’s background is actually as a physicist. “I’m a physicist trying to build a drug development company,” he says. “It gives me an outsider’s view toward drug development, but it’s informed by very, very deep drug development knowledge and expertise. We’re very excited to see how it evolves and what we can contribute to drug development.”

He also points out that this mix of biology and engineering is reflected by the investors. “We have very deep pharma investors and deep technology investors, which is a recognition of the technical part of our tech program, very deep pharma expertise merging with deep engineering expertise.”