"We want to build the Genentech of small molecules, and we want to do it San Diego," Vividion Therapeutics Inc. CEO Diego Miralles told BioWorld, as the company made public a deal that brought $101 million up front from Celgene Corp., which included an equity investment as part of the amount.

San Diego-based Vividion and Celgene, of Summit, N.J., will pursue "a handful" of small molecules against targets for a range of oncology, inflammatory and neurodegenerative indications, Miralles said. Terms call for four years of work, with Celgene potentially extending the pact for another payment, the amount of which the companies left unspecified. The Celgene collaboration is intended to advance small molecules that function through the ubiquitin proteasome system, modulating specific protein levels for therapeutic benefit.

"We can do anything but we cannot do everything," Miralles said. A strategic approach "requires that we choose some areas of focus where our expertise is going to lie," while doing "partnerships in many other areas where the product engine can provide drugs."

As structured, the tie-up with Celgene "offers exceptional flexibility to pursue anything we would want to, except for that limited number of targets" specified in the terms, he said. "There are 19,000 proteins in the human proteome and I would say that 99.999 percent of the proteins remains free for us to pursue. It's very important to us to have wholly owned programs that go to the market. We could create an inexhaustible pipeline and we wanted to make sure that the deal did not constrain that potential."

Where Vividion might go next with its own research is yet to be made known. "We are actively having those discussions and we hope we will be able to disclose more in the near future," he said.

Vividion launched about a year ago with a $50 million series A round, planting its foundation in 2014 on the work of scientist Ben Cravatt, chair of the Department of Chemical Physiology at The Scripps Research Institute (TSRI), whose work focused "on the really fundamental problem in drug discovery," that is, getting beyond the conventional target-centric approach that typically nets a limited number of hits and leads. Efforts by Cravatt and his team at TSRI, published in 2016 in Nature, demonstrated a method of widening that net by developing a way to find ligands – the binding partners – for proteins previously believed to be undruggable. Using a fragment-based ligand discovery approach, researchers attached those fragments to molecules that bind covalently to the amino acid cysteine. What they found was that the human proteome contains many "ligandable" cysteines, including in proteins not shown previously to interact with small molecules.

Arch Venture Partners and Versant Ventures co-led the series A. (See BioWorld Today, Feb. 2, 2017.)

"We can go after any target, the same way an antibody company can go after any target, but with the advantage that small molecules are really the only global treatment, the only universal treatment," Miralles said. "You can treat somebody in a village in Indonesia as much as you can treat them in La Jolla. There's no other therapeutic platform that can do that."

It's a departure from the usual route. "Traditionally, the way that small molecules have been used is to fit into catalytic pockets, where there's an occupancy that prevents the interaction with a natural substrate with that pocket," Miralles said. "We discover sites in the proteome that can be liganded. Effectively, you can put a hook into a protein. That hook can be used in many different ways. It could be to develop drugs that have an allosteric effect, or that affect protein-protein interactions. At the same time, because you have a hook, you have a ligand on that protein, [so] you can drug that protein to degradation."

Most developers, Miralles said, are "using existing drugs, putting them together on bispecific molecules, and then degrading those substrates. What the space needs, on the substrate side, is ligands to new proteins that have been undruggable [until] today."

Vividion accomplishes that and more, he said. "Not only can we create ligands against any substrate and a lot of novel substrates that have not been drugged before, but we can also create ligands on the E3 ligase side, some of those 600-plus E3s that have not been drugged. We bring innovation on both sides of that bispecific molecule," a move that "opens a whole range of possibilities as to what can be done. Another big promise of protein degradation is that we can discover E3 ligases that are tissue specific, or cell specific, or cell state specific," he said, adding that such is just "one of the applications of the platform that we're going to be working on. We have several targets that are part of the deal [where] we're going to be working on functional effects, not necessarily only on protein degradation."

In the future, how much of Vividion's model involves partnering and how many resources will be devoted to internal work is "a work in progress," Miralles said. "As we move along, we will determine what the right allocation is. All I can say is that a significant number of exceptional [would-be] partners have been at the table with us. It was really hard to make a choice." Celgene emerged as one with an especially "deep knowledge of the biology that we work on," he said.