C4 Therapeutics

Fierce 15

Using a new class of small molecule targeted protein degradation therapeutics that go after disease-causing proteins and boost their rapid destruction and clearance from the cell

President and CSO: Andrew Phillips
Based: Cambridge, MA
Founded: 2016
Clinical focus: Targeted protein degradation using degronimid technology with an initial focus on cancer targets

The scoop: C4 Therapeutics is one of only a handful of companies working on tackling protein degradation using small-molecule binders--dubbed degronimids--that can target, destroy and clear proteins through the ubiquitin/proteasome system. While preclinical, the biotech is confident its approach will have a major impact on cancer, as well as a host of other diseases.

What makes C4 Therapeutics Fierce: Jason Fisherman, the biotech’s CEO, venture veteran and a former researcher at the National Cancer Institute, tells FierceBiotech: “We’re rapidly building C4 to be the leader in tackling protein degradation. Our mission is to discover and develop drugs to advance the treatment of cancer, as well as other life-impairing diseases. We were founded at the start of the year [2016] by a group of distinguished scientists and doctors from Dana-Farber in Boston and from the seminal work coming out of Jay Bradner’s work [who is now working at C4 investor Novartis] with Ken Anderson, a pioneer in the [immunomodulatory drugs] IMiD class of drugs for multiple myeloma.

“They came together at the start of the year with a $75 million investment and with a deal from Roche that could also be worth $750 million, so this was a sizable and highly validating deal right out of the gate--I don’t know many other startups that have the same origins story. This was in January, so fast-forward to August and we’ve already recruited a very experienced leadership team and now grown the company to 40 full-time employees.

“We live here in 20,000 square feet of space in Kendall Square, and we’ve now got a group of outstanding drug discovery scientists from great academic institutions like the Dana-Farber, MD Anderson, MIT, along with folks with substantial industry experience from places like Merck, AstraZeneca, and Vertex, as well as a number of different smaller biotechs. So we’ve got a great mix of experience, innovation and depth.”

So what are they doing with all this space and scientists that have turned the heads, and opened the wallets, of the likes of Roche? The work is centered on its degronimid platform, which uses an all-chemical solution that is designed to allow for powerful, targeted, rapid protein degradation. They work as chemical adapters that are conjugated with selective small molecules designed to recruit the cell’s ubiquitin/proteasome system in order to “naturally” degrade targeted proteins.

In May last year, Bradner published his work on degronimids, illustrating how enzymes that attach ubiquitin to them could tag target proteins and then drag them to a proteasome for disposal and recycling. The approach was successfully used on cancer cells, and the big hope is that these will be the key for the removal of previously undruggable proteins, including those that are known to develop resistance to inhibitors.

Fisherman says: “We’ve built the company around three specific areas of capability: small molecules, target biology (specifically in cancer) and technologies that explore the ubiquitin/proteasome system in a really deep and detailed way to really understand how the program of this very complex degradation machine works, and to engineer specificity into our drug candidates.”

This native, internal cellular machine that regulates protein homeostasis and tags and directs proteins into the degradation, or as Fisherman puts it, the “recycling factory,” where proteins are broken down into their components, is the opportunity the biotech sees as being a rich hunting ground for invention.

“This whole field of targeted degradation offers the potential for very novel and distinct pharmacology which can then be deployed against resistant and refractory disease targets, and along with proteins that offer no ready access to their active site, which is required for the design of traditional small-molecule inhibitors. When we think of a disease area, the focus of our initial research, given our roots, is clearly in oncology [although targets have not yet been disclosed], but we’re also keen to be involved in other areas, such as neurologic disease, CV disease, GI and infectious diseases--and we’ll be looking to grow in those areas both on our own, and with partners in the future.”

Not yet in the clinic, the biotech envisions first human testing as early as 2018, with activated cell therapy and immuno-oncology slated to be in the mix for these trials in the not-too-distant future, according to Fisherman.

All at an early stage, cancer specialist Celgene is working in this space, as is 2015 Fierce 15 company Arvinas, a Yale spinout, who is also setting its sights on protein degradation.

Investors: Cobro Ventures, Roche, Novartis, Cormorant Asset Management, The Kraft Group and EG Capital Group

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C4 Therapeutics

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