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Drug Discovery

Stablix debuts to develop drugs that stabilize protein function

The biotech firm aims to develop bifunctional small molecules for rare diseases, cancer, and immunology

by Lisa M. Jarvis
June 3, 2021 | A version of this story appeared in Volume 99, Issue 21


Stablix Therapeutics has launched with $63 million in funding to explore drugs that can rescue proteins otherwise destined for the cellular waste bin.

The New York City–based biotech firm turns on its head the concept of targeted protein degradation, in which researchers design drugs that force bad-behaving proteins into the proteasome, the cell’s trash can. Typically, one end of those heterobifunctional small molecules binds to a protein of interest. The other binds to an E3 ligase, an enzyme that kicks off a chain of events that ends in the addition of a ubiquitin to the protein. The ubiquitin tags the protein to be broken down in the proteasome.

Stablix wants to design molecules that pluck off that tag, restoring function to proteins otherwise destined for the trash. One end will bind to a protein of interest, while the other will tether to a deubiquitinase (DUB). About a hundred DUBs in the genome regulate the roughly 100,000 proteins in the body, and one of Stablix’s skills is the ability to quickly vet DUBs for the right match to a protein.

Although Stablix’s molecules will perform the opposite task as a protein degrader, the firm benefits from the years spent understanding the properties needed to turn molecules that tap the ubiquitin-proteasome system into actual drugs, says Carlo Rizzuto, acting CEO and a partner at Versant Ventures, which led the funding. Since 2019, a handful of protein degraders has entered clinical studies.

Stablix plans to develop protein-stabilizing drugs for three therapeutic areas: rare diseases driven by a single genetic mutation; cancers in which E3 ligases are amplified, causing tumor-fighting proteins to be tagged for breakdown; and immunology.

The research that inspired Stablix originated in the labs of Columbia University’s Henry Colecraft, an expert on ion channel dysregulation. Colecraft showed that mutated proteins not only stick around after a ubiquitin tag is removed but that they even retain their function, says Brian Bowman, Stablix’s cofounder and head of in vitro pharmacology.

Rizzuto says a few other pieces of evidence convinced Versant that the approach had merit. For one, “viruses do this all the time,” he says. Viruses encode their own deubiquitinases or E3 ligases, or can co-opt the enzymes from the cell to work on their behalf.

And a class of cancer drugs called proteasome inhibitors is known to restore function in proteins linked to other diseases, such as certain forms of muscular dystrophy. But those molecules “are basically sledgehammers,” shutting down all protein degradation in the cell, Rizzuto says. That approach works in cancer, where the side effects from such global activity can outweigh the benefits. In theory, Stablix’s heterobifunctional molecules will act like tweezers on the tags of specific protein types.



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