As new technologies give drug developers greater insight into protein biology, more biotech and pharma companies are now emboldened to pursue what have long been dismissed as undruggable targets—the 75-85 percent of all human proteins that are beyond the reach of today’s medicines. One more startup is joining the quest to find small molecule drugs that act on these elusive targets: Cedilla Therapeutics, which today announced a $56 million Series A round from Third Rock Ventures. The Cambridge, MA-based company, like a few others, wants to use small molecules to trigger the destruction of disease-causing proteins by the cell.
One way that cells normally rid themselves of misfolded or damaged proteins is by tagging them with molecules called ubiquitin. Proteins that are marked by ubiquitin get sucked into the cell’s garbage disposal called the proteasome—a biochemical version of a paper shredder. Several startups including Arvinas and C4 Therapeutics are designing drugs that cause targeted proteins to get tagged by ubiquitin for destruction by the proteasome. But Cedilla is taking a different approach—aiming its drugs at “upstream” biochemical events that happen to proteins even before they get that fatal ubiquitin stamp. The aim is for disease-causing proteins to ultimately go through the protein shredder or get degraded through other pathways.
So what are these upstream events? As Cedilla’s chief scientific officer Brian Jones explained, proteins can switch from a stable to a “susceptible” state, where they are vulnerable to degradation, even before ubiquitin comes into play. These proteins become vulnerable in various ways: for example, when they are chemically modified (or prevented from being modified) in some way, or become bent out of shape, or when they are yanked away from the comfort and protection of larger groups of proteins. Cedilla’s goal is to find small molecules that, in one way or another, disrupt the processes that keep proteins stable. The result would hopefully be to make disease-causing proteins vulnerable and put them on the path to destruction.
Cedilla CEO Alexandra “Sandra” Glucksmann says targeting biochemical events that are upstream of the ubiquitin-tagging process gives her company flexibility to go after a wider range of protein targets. “We are closer to the targets,” allowing her team to focus first on the best targets based on their biology, rather than focusing first on the underlying technology, says Glucksmann.
Glucksmann says Cedilla is working on drugs targeting cancer-driving proteins. But she adds that she doesn’t want her company to just churn out small-molecule products. “We’re also about really defining the rules and principles that define protein stability, in order to select additional targets,” says Glucksmann, adding that Cedilla’s approaches could be applicable to neurodegeneration and genetic diseases.
The promise of using protein degradation as a therapeutic approach was not lost on the pioneering scientists who first started looking into the possibility about two decades ago. Craig Crews of Yale founded Arvinas in 2013, and Jay Bradner co-founded C4 Therapeutics in early 2016 before he moved from the Dana-Farber Cancer Institute to head up the Novartis Institutes for Biomedical Research. Both companies are developing drugs that recruit key components of the ubiquitin-proteasome system to targeted proteins, leading to the proteins’ destruction. Both have large partnerships with pharma companies. Atlas Venture launched its own company in this area, Kymera Therapeutics, late last year.
Even in such a crowded area, Glucksmann and Jones say that there’s plenty of room in the undruggable proteome for multiple companies, including theirs, to operate.
Cedilla has been incubating at Third Rock for about 18 months. Glucksmann joined the venture firm as an entrepreneur-in-residence late last year to head up the company, after serving as chief operating officer of gene-editing firm Editas Medicine (NASDAQ: [[ticker:EDIT]]). Jones joined Third Rock about a year ago, after leading teams in basic and medicinal chemistry at Novartis (NYSE: [[ticker:NVS]]) in Cambridge, MA, and Merck (NYSE: [[ticker:MRK]]).
Glucksmann declined to say when her team would reach the clinic, but says she plans to more than double the size of her 12-employee company by the end of this year.
