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small molecules—chemical compounds—that enter a cell and “trick” the UPS system into tagging an undesirable protein as trash and discarding it.
The UPS system has two parts: ubiquitin, which tags proteins for removal; and the proteasome, which disposes of them. A degronimid has two binding molecules, or ligands, on it. Think of them as two hands. One grabs a tagging molecule, and the other a protein C4 wants to mark for destruction. A degronimid brings the two together, so the bad protein is flagged and the protein is hauled off to the proteasome and destroyed. C4 can customize them to latch on to a variety of different proteins. (The approach was featured in a May 2015 paper in Science.)
“We’re really letting the body do the heavy lifting here,” Cohen says. “All we’re doing is the matchmaking.”
By actively flagging unwanted proteins, C4 hopes to destroy ones that other drugs haven’t been able to. The company also believes tumors hit with this approach won’t be able to build up resistance to the drugs, a common problem with cancer. Cohen says the key is to destroy the proteins, not just block their functions and let them live to see another day—which is valuable time to mutate and figure out a new way to do their job.
“We’re taking that disease causing protein and we’re blowing it out of the water,” he says. Hence the name C4, a type of plastic explosive. “And it happens quickly so we believe that the likelihood of mutation-based resistance is going to be significantly diminished.”
Jason Fisherman, a veteran biotech investor most recently at Synthesis Capital, has been named C4’s CEO in conjunction with the financing. The company will soon move its work out of Dana-Farber and into Mass Innovation Labs in Kendall Square, which opened last year in one of the buildings that used to be home to Vertex Pharmaceuticals (NASDAQ: VRTX).