Decades ago scientists identified a particular class of proteins driving illnesses from cancer to neurodegenerative disease. These “intrinsically disordered proteins” (IDPs) looked different from the proteins with rigid structures that were more familiar in cells. IDPs were shape shifters, appearing as ensembles of components that constantly changed configurations. This loose structure turns out to allow the IDPs to bring together a wide variety of molecules at critical moments, such as during a cell’s response to stress. Less flexible proteins tend to have a more limited number of binding partners. When IDPs do not function properly, disease can ensue.
Yet medical researchers have not been able to create treatments to eliminate or regulate malfunctioning IDPs. Indeed, many have been called undruggable. That is because most medicines now in use require stable structures to target, and IDPs do not stay put long enough. Well-known disordered proteins that can contribute to cancer—including c-Myc, p53 and K-RAS—have proved too elusive. But this picture is starting to change.
Scientists are using rigorous combinations of biophysics, computational power and a better understanding of the way that IDPs function to identify compounds that inhibit these proteins, and some have emerged as bona fide drug candidates. In 2017 researchers in France and Spain demonstrated it is possible to aim at and hit the changeable “fuzzy” interface of an IDP. They showed that an FDA-approved drug called trifluoperazine (which is used to treat psychotic disorders and anxiety) bound to and inhibited NUPR1, a disordered protein involved in a form of pancreatic cancer. Large-scale screening tests to evaluate thousands of drug candidates for therapeutic potential have revealed several that inhibit c-Myc, and some are moving toward clinical development. Additional molecules have been identified that work on IDPs such as beta-amyloid, implicated in diseases such as Alzheimer’s.
This list will continue to grow, especially as the role that IDPs play in crucial cell parts known as membraneless organelles becomes clearer. Often called droplets or condensates, these organelles bring vital cellular molecules—such as proteins and RNA—close together at specific times, while keeping others apart. Proximity allows certain reactions to occur more easily; separation prevents various reactions. Scientists have designed powerful new molecular manipulation tools, which go by the names Corelets and CasDrop, that allow researchers to control how these droplets form. Using these tools and others, researchers have learned that IDPs may help control droplet assembly, function and disassembly.
This discovery is important because during droplet formation and breakdown, IDPs interact with various binding partners and sometimes hold new shapes for a few moments as they do so. It may be easier to find drugs that find and bind to those shapes than it is to find compounds that can hit IDPs in their other guises. Researchers across the globe are pioneering efforts to uncover these droplet-related mechanics.
Industry is also betting on the therapeutic potential of IDPs. Biotechnology company IDP Pharma is developing a type of protein inhibitor to treat multiple myeloma and small-cell lung cancer. Graffinity Pharmaceuticals, now part of NovAliX, has identified small molecules to target the disordered protein tau, which is involved in Alzheimer’s pathology. Cantabio Pharmaceuticals is on the hunt for small molecules to stabilize IDPs involved in neurodegeneration. And a new company called Dewpoint Therapeutics is exploring the idea that droplets and their disordered components, because of the way they bring molecules together for enhanced reactions, could be used as drug targets.* It is increasingly likely that in the next three to five years these once “undruggable” proteins will end up in the crosshairs of pharmaceutical development.
Editor’s Note (7/10/19): This sentence was edited after posting. It originally said that droplets and their disordered components could be used as drugs themselves.