Cedilla Therapeutics Inc., a startup harnessing protein stability mechanisms to broaden the reach of small-molecule drugs in cancer and other diseases, is debuting with $56.2 million in series A funding from Third Rock Ventures. The Cambridge, Mass.-based company, created last summer by academics at Harvard and University of California San Francisco and led by former Editas Medicine Inc. chief operating officer Alexandra Glucksmann, is seeking new points of intervention for diseases caused by protein dysregulation.

Protein involvement in disease can take many forms, including overexpression, misfolding or incorrect post-translational modifications, Glucksmann said. As a common thread, though, all proteins have a half-life transition from a stable to an unstable state. It's at that point that they're most vulnerable to degradation and where Cedilla is most likely to look for opportune points to intervene.

While it's too early to identify the specific indications in which Cedilla will work or the company's initial clinical goals, she laid out an ambitious agenda, including a doubling of the company's staff to 25 by year-end and a program of parallel development intended "to uncover the principles, or rules, that govern protein stability."

The team's key methods comprise a fourfold approach that appears to offer it significant latitude in achieving that end, starting with direct ligand-induced degradation, and moving on to upstream regulation, protein "orphaning" and protein susceptibility mapping. Starting in cancer, the 12-person team will seek small molecules that bind to proteins to induce conformational change and induce degradation. It will also employ high-throughput cell-based screening to identify upstream proteins that may regulate its targets of interest.

On an alternative but related path, company scientists might look to affect the properties of a protein's "partner" by identifying pharmacologically accessible interactions between proteins and multiprotein complexes pivotal in the stability of a target protein.

In addition, the company is implementing a large-scale proteomics mapping initiative. In that realm, Glucksmann said, scientists are treating cells with agents that may induce change and then looking at cellular proteins using mass spectrometry to identify the proteins most susceptible to degradation.

Third Rock has been interested in the protein stability space for quite a while, Glucksmann said. After engaging in 2017 with Bill Kaelin, a professor at Dana-Farber Cancer Institute and Harvard Medical School, and Alan D'Andrea, also a professor at Harvard Medical School and director of the Center for DNA Damage and Repair at Dana-Faber Cancer Institute, those conversations matured. With additional scientific co-founders looped in, Glucksmann joined Third Rock in October, knowing she would head Cedilla. Named for the transformational power of the diacritical mark, the company will now use its new funding to get to a "unique value inflection point," she said.

The field of protein degradation and stability has drawn interest from a number of companies in recent years. New Haven, Conn.-based Arvinas LLC, a company started with backing from Canaan Partners and 5AM Ventures, has attracted attention with its PROTAC (PROteolysis TArgeting Chimeras) platform, the subject of two multimillion-dollar partnerships, first with Merck & Co. Inc. and later with Pfizer Inc. (See BioWorld Today, April 8, 2015, and Jan. 4, 2018.)

Atlas Venture-backed Kymera Therapeutics LLC, another Cambridge, Mass.-based company, has also attracted outside interest, landing a two-year discovery collaboration agreement with London-based Glaxosmithkline plc in April, built around the its E3 ligase-based Pegasus drug discovery platform. Financial details of that agreement were not disclosed. (See BioWorld, Oct. 31, 2017.)

Cambridge, Mass.-based C4 Therapeutics Inc. and Burlingame, Calif.-based Cleave Biosciences Inc. have also been active in advancing programs. San Francisco Nurix Inc., established by Third Rock with The Column Group in 2014, has been fairly quiet, but according to regulatory filings, remains engaged in a strategic collaboration with Summit, N.J.-based Celgene Corp. to advance new therapies that function through the ubiquitin proteasome system to modulate protein homeostasis.