When proteins within the body get tagged with a molecule called ubiquitin, they are essentially marked for destruction. But they can be saved; a deubiquitinase enzyme can remove the ubiquitin, keeping the protein intact. That, at least in part, is what Entact Bio aims to do.
Entact launched on Dec. 6 with $81 million in funding to develop two-ended small molecules that strip the ubiquitin from a beneficial protein. One end of the molecule binds the protein while the other binds a deubiquitinase, drawing the two compounds together so that the enzyme can remove the ubiquitin tag. The protein is spared from destruction.
But the company isn’t just trying to stop ubiquitin from sending proteins to the cellular garbage disposal. Rather, it’s looking at the “full spectrum of ubiquitin function,” emphasizes CEO Victoria Richon. There are different ubiquitin chains on proteins, and they can signify different things, she says. They can mark a protein for disposal, or they can interfere with a protein’s ability to interact with another protein. They can also cause a protein to be in the wrong place within the cell.
“We know that ubiquitin is doing a lot more than just sending proteins for destruction,” she says.
In other words, the company strives to keep good proteins intact and also to ameliorate the other impacts of ubiquitination. The name Entact—a spin on both intact and enhance—reflects this goal. The firm has named its bifunctional compounds “enhancement-targeting chimeric molecules,” or ENTACs.
The Massachusetts-based start-up joins a growing field of companies leveraging deubiquitinases. Vicinitas Therapeutics, which launched in July, and Stablix Therapeutics, launched in June 2021, both employ double-ended molecules to pull a deubiquitinase into proximity with a ubiquitinated protein, preventing the protein’s destruction. Neither firm has a drug candidate in clinical trials. Similarly, ENTACs join Vicinitas’s deubiquitinase-targeting chimeras (DUBTACs), and Stablix’s RESTORACs in the growing vocabulary of bifunctional molecules that leverage deubiquitinase enzymes.
This class of molecule is the opposite of the more common proteolysis-targeting chimeras (PROTACs), which, also double-ended, draw together a badly-behaving protein and an enzyme that will get it tagged with ubiquitin, marking it for disposal.
The scientific founders of Entact bring expertise in proteomics, biochemistry, structural sciences, ubiquitin signaling, and more, Richon says. The start-up’s series A financing round was co-led by Qiming Venture Partners USA and venBio Partners, the latter of which has funded firms like Turning Point Therapeutics, Rayze Bio, and Arrakis Therapeutics.