It took 23 years from the isolation of the gene for cystic fibrosis to the approval of the first drug to target it, and another 7 for a drug that could treat the vast majority of CF patients. Third Rock Venture’s latest startup thinks they can build similar drugs a whole lot faster.
MOMA Therapeutics has raised $86 million to investigate and drug a class of enzymes known as molecular machines. These proteins include everything from enzymes involved in DNA repair to the transport proteins that go awry in cystic fibrosis — over 400 different types, by MOMA’s count. And yet, MOMA contends, they have been overlooked to date, with researchers both failing to understand them as a cohesive group and failing to employ systematic ways of finding and drugging them.
Vertex’s CF drugs and proton-pump inhibitors, both of which go after machines, are red herrings, MOMA wrote in a blog post accompanying the launch: Their success is a sign of both the field’s potential and biopharma’s overall failure.
“Not only do these medicines further underscore the therapeutic potential of these enzymes,” MOMA wrote, “they also illustrate biopharma’s rudimentary approaches to prosecuting them — nearly all were discovered from natural products, through serendipity or without a systematic approach to interrogating the biochemistry of the proteins themselves.”
Although the young biotech has yet to announce any targets, the blog post points emphasizes the role of these molecular machines in cancer and rare diseases. Like most Third Rock startups, it will be led by a firm partner: in this case, Reid Huber, who most recently served as CSO of Incyte. And the company’s R&D efforts will be led by Blueprint veterans Christoph Lengauer and Tim Guzi, who step in as CSO and SVP of drug development, respectively.
The company’s approach comes largely out of the Howard Hughes Medical Institute, where Dorothee Kern, Eva Nogales and Johannes Walter collaborated. A fourth founder, Third Rock entrepeneur-in-residence Timur Yusufzai, will head up protein sciences at the biotech.
Molecular machines are, as the New York Times once put it, the world’s smallest mechanical devices. Scientists have just begun synthesizing artificial ones, but hundreds of different types of these puny motors are running in the body at every minute, breaking down and building DNA, ferrying salt and water into and out of cells, forcing muscles to relax and contract.
Normally, these motors function by shifting between isoforms — different structures with the same chemical makeup. But a single mutation, such as those seen on the CFTR molecular machine in cystic fibrosis, can act like a faulty valve, causing various degrees of malfunction. Tumors, meanwhile, can sometimes depend heavily on one of these motors to grow.
Their structural changes are their weakness, Huber told Endpoints News. Although all proteins change shape, molecular machines do so at an unparalleled scale. MOMA will search for those machines with genomic data and try to use small molecules to intervene, potentially correcting malfunction in rare diseases and crippling tumors.
“Think of it like the difference between walking to the mailbox at the end of the driveway vs. getting in a car and driving to Ohio — molecular machines are the latter. They open, they close, they twist, they slide, they unwind on a massive scale — all in order to produce work,” Huber wrote in an email. “This unique dependence on such large changes in shape provides the key opportunity for MOMA Tx — if we can disrupt those changes with small molecules, we may be able to discover novel medicines and do it in a systematic way across the entire class.”