Interview – C4 starts life with a bang

Companies with novel cancer candidates often manage to reel in the big bucks, and C4 Therapeutics is no exception. A $73m series A round in January made it 2016’s second-biggest fundraiser so far and the latest player to target the ubiquitin proteasome system (UPS), the cell’s so-called trash can.

C4’s technology allows it to select proteins for ubiquitination – a way of “tagging” them for disposal. The group’s products could have myriad uses because “nature targets literally everything [it wants to get rid of] with ubiquitin”, the group's chief scientific officer, Andy Phillips, tells EP Vantage. “What is new is the idea we can develop tools to selectively target proteins for ubiquitination.”

“Cancer is one of the areas of focus,” adds chief business officer Tom Needham. “But there are many areas outside cancer that could be pursued.” However, as a small company it is unrealistic for C4 to look into all of these itself, so while it has its own internal pipeline it is also searching for partners.

It already has one: Roche, which invested in the series A round along with Novartis. The Roche partnership, potentially worth over $750m, gives the Swiss company rights to preclinical C4 candidates that hit “a specific set of target proteins”.

The C4 executives will not say what these targets are, or give any more details on the targets for internal projects. But more broadly Mr Phillips does say that potential targets could include aberrant proteins that arise from cancer-driving gene mutations. “We’d be looking for a molecule that binds the mutant but doesn’t bind the wild type,” he says.

There are also disorders where there is either too much or too little of a protein. Neurodegenerative diseases seem an obvious example – if the UPS could be harnessed to get rid of unwanted proteins it might be able to clear the amyloid-beta that builds up in the brain of Alzheimer’s patients, for instance.

Delivering with UPS

This secrecy perhaps makes sense as this is still a young area of science, probably with all the intellectual property wrangling that comes with the territory. While the UPS has been known about for around 30 years, C4’s Degronimid technology is based on research by its co-founder, James Bradner, at the Dana-Farber Cancer Institute and published in Science last year.

Put simply, C4’s candidates are designed to work “by recognising a protein of interest, grabbing it with one arm, then grabbing the ubiquitination machinery with the other arm and bringing them together in close proximity”, Mr Phillips explains. “Then the ubiquitin is transferred to the protein of interest and then that protein is ultimately ubiquitinated further and degraded.”

The Cambridge, Massachusetts group’s projects have three components: a molecule that binds to the protein of interest, a linker, and a molecule that binds to this so-called ubiquitination machinery. The ubiquitination machinery that C4 is harnessing is the cereblon E3 ubiquitin ligase complex.

There are several approved drugs that work on the UPS, such as Velcade and Kyprolis, but they inhibit the system – whereas C4’s candidates “don’t disrupt the proteasome; we just leverage it to dispose of faulty proteins”.

“Velcade and Kyprolis are the equivalent of pulling the plug out on the waste disposal unit,” says Mr Phillips. The idea is that this causes a build-up of unwanted proteins in the cell, which eventually kills the cancer cells.

Resistance

However, one problem with the proteasome inhibitors is the eventual emergence of resistance. C4 believes that its candidates will reduce this issue – mainly as the faulty proteins will not be present long enough for tumour cells to develop a tolerance to them.

Other companies in this space are also at an early stage, but many have already attracted interest from big pharma. The most similar to C4 seems to be Arvinas, which is developing what it calls proteolysis-targeting chimaeras (PROTACs) to target proteins for removal from the cell.

One end of the PROTAC binds to the target protein, while the other binds E3 ligase, the ubiquitination machinery. Arvinas’s candidates are at the preclinical stage, but it already has an R&D partnership with Merck & Co, and in October it raised $41.6m in a series B round.

Nurix, meanwhile, is developing candidates either to activate or to inhibit the UPS system, and has teamed up with Celgene in a deal that encompasses immunology, oncology and inflammation.

Groups in the wider proteostasis sector include Italy’s Forma Therapeutics, Proteostasis Therapeutics and Mission Therapeutics, which all have candidates targeting deubiquitinating enzymes (DUBs). As DUBs reverse the ubiquitination process, inhibiting these promotes degradation of target proteins (Interview – 2016’s biggest fundraiser on a Mission, March 30, 2016).

“This is probably not an exhaustive list,” Mr Phillips says. “As you can imagine, many large pharmaceutical companies are now thinking, ‘Boy, what could we do?’”

He is confident that the space is big enough to support many groups. “There’s a lot of green pasture for us and others to use this approach as a new drug modality – and a lot of different targets, and multiple therapy areas. If it works it’s going to work broadly, and there’s going to be plenty of room and lots of competition.”

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow  @medtech_ma on Twitter