Rare Daily Staff
Stablix Therapeutics launched with $63 million in series A financing to target protein stabilization, a new modality for developing therapies for diseases caused by insufficient levels of specific proteins.
Founding investor Versant Ventures led the financing together with NEA, Cormorant, Euclidean Capital and Alexandria Real Estate Equities.
Many inherited and acquired diseases are caused by insufficient levels of specific proteins. With inherited diseases such as cystic fibrosis, mutations in the CFTR gene produce a protein that remains functional but is subject to excessive ubiquitination, leading to its rapid degradation via the proteasome. Excess ubiquitination is also a feature of cancer, where E3 ubiquitin ligases—enzymes that add ubiquitin to proteins—are frequently upregulated or amplified, driving the degradation of tumor suppressor proteins.
Until now, it has not been possible to inhibit the ubiquitin-proteasome system in a target-selective manner. Stablix’s RESTORED platform generates heterobifunctional small molecules called RESTORACS that recruit deubiquitinase enzymes to remove ubiquitin from targeted proteins and consequently stabilize or increase target protein levels and activity. The company initially is leveraging the platform to develop programs to treat rare diseases, cancer, and immunological disorders.
“Stablix possesses a first-in-category platform that can restore protein stability and function in a target-selective manner,” said Carlo Rizzuto, partner at Versant and acting CEO of Stablix. “We are very pleased to launch this company to address this important therapeutic white space for numerous devastating diseases.”
Protein stabilization can be thought of as the inverse of protein degradation. The underlying concept of augmenting protein stabilization has been validated in nature. Many viruses encode their own E3 ligases and deubiquitinases to coopt the ubiquitin-proteasome system as part of their life cycles. This demonstrates that the system can be manipulated via exogenous intervention.
The therapeutic value of augmenting protein stabilization has also been demonstrated with proteasome inhibitors. These inhibitors are potent cancer therapeutics but have also been profiled for activity in Mendelian diseases in multiple animal and patient studies. In these studies, proteasome inhibitors were able to increase levels of deficient proteins across a range of targets and organ systems. However, because proteasome inhibitors globally inhibit protein degradation in a non-specific manner, their use outside of oncology is limited by poor tolerability, highlighting the need for targeted approaches.
The Stablix platform originated in the laboratory of Henry Colecraft, John C. Dalton Professor of Physiology and Cellular Biophysics at Columbia University. Co-founders Colecraft and Scott Kanner developed an approach to selectively recruit deubiquitinases (DUBs) to proteins of interest. Their pioneering work demonstrated the functional rescue of CFTR and of a second target, KCNQ1, a gene that when mutated causes Long QT syndrome.
The company’s RESTORED platform has two primary components. The first is a library of binding moieties capable of recruiting selected DUBs. These recruiting moieties are conjugated with linkers to targeting ligands to create bispecific molecules that co-localize a DUB and a target. Second, a suite of biochemical and functional assays is used to monitor the ubiquitination and functional status of target proteins in cells. Stablix will initially focus pipeline development on rare diseases, oncology, and immunology.
Stablix plans to use the proceeds from the series A financing to build out its platform and advance a portfolio of protein stabilizers towards the clinic. In addition, the company has established a lab facility in New York City, where it is building a research team led by co-founders Brian Bowman, head of in vitro pharmacology, and Kevin Sprott, head of drug discovery, with Kanner, head of platform development, leading technology transfer.
Photo: Carlo Rizzuto, partner at Versant and acting CEO of Stablix