A key property needed for the effectiveness of CELMoD drugs, a type of protein degrader, has been discovered.
Scripps Research Institute scientists have discovered a crucial feature that is necessary for CELMoDs, a promising new class of cancer drugs, to work effectively.
CELMoDs are a new class of cancer drugs that function by binding to cereblon, a regulatory protein, which causes the degradation of proteins that drive cancer. Researchers found that for CELMoDs to work effectively, they must cause a specific shape change in cereblon upon binding. This discovery, recently published in the journal Science, allows for the reliable design of effective CELMoDs.
“There are a lot of research groups that have spent considerable time making drugs that bind very tightly to cereblon, but have then scratched their heads in puzzlement that these drugs fail to work,” says study senior author Gabriel Lander, Ph.D., professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
Cereblon works as part of a major protein-disposal system in cells. This system tags targeted proteins with molecules called ubiquitin, which mark the proteins for destruction by roving protein-breaking complexes known as proteasomes. The ubiquitin-proteasome system is used not only to destroy abnormal or damaged proteins, but also to help regulate the levels of some normal proteins. Cereblon is one of the hundreds of “adaptors” used by the ubiquitin-proteasome system to guide the ubiquitin-tagging process toward specific sets of target proteins.
Scientists now recognize that some cancer drugs, including the best-selling myeloma drug lenalidomide (Revlimid), happen to work by binding to cereblon. They do so in a way that forces the ubiquitin-tagging, and consequent destruction, of key proteins that promote cell division—proteins that couldn’t be targeted easily with traditional drugs. Inspired in part by that recognition, drug companies have begun developing cereblon-binding drugs—CELMoDs, also called protein-degradation drugs—that will work even better against myeloma and other cancers.
One enduring problem for the field has been the fact that some of these drugs bind tightly to cereblon, yet fail to cause sufficient degradation of their protein targets. Understanding why this happens has been difficult. Scientists have wanted to use high-resolution imaging methods to map cereblon’s atomic structure and study its dynamics when bound by CELMoDs. But cereblon is a relatively fragile protein that has been hard to capture with such imaging methods.
In the study, Watson spent more than a year devising a recipe for stabilizing cereblon in association with a ubiquitin-system partner protein, in order to image it with low-temperature electron microscopy (cryo-EM). In this way, he was able ultimately to resolve the cereblon structure at a near-atomic scale. Watson also imaged the cereblon-partner complex with CELMoD compounds and target proteins.
The structural data revealed that CELMoDs must bind to cereblon in a way that changes its shape, or conformation. Cereblon, the researchers determined, has a default “open” conformation, but must be switched to a particular “closed” conformation for the ubiquitin-tagging of target proteins.
The main significance of the finding is that drug companies developing CELMoDs now have a much better idea of what their candidate drugs must do to be effective.
“Companies have been developing cereblon-binding protein-degradation drugs that they can see are better degraders, but they didn’t know this was because the drugs are better at driving this closed conformation,” Watson says. “So now they know, and they can test their drugs for this key property.”
Watson’s breakthrough recipe for stabilizing cereblon in preparation for cryo-EM imaging also is now being adopted widely by researchers in this field.
Lander says his lab hopes now to facilitate the development of protein-degradation drugs that work by binding to other ubiquitin-proteasome adaptor proteins besides cereblon. As he notes, the big attraction of the protein-degradation drug strategy is that it can be used to hit virtually any disease-relevant protein, including the very large class of proteins that can’t be targeted with traditional drugs.
DREAM complex could hold key to fighting cancer and living longer
DNA may be the stuff of life, but if it isn't repaired in our bodies on a regular basis, it can lead to diseases that can cause some pretty unpleasant types of death. DNA [...]
A Promising New Pathway in the Battle Against Aggressive Prostate Cancer
Neuronal Molecule Makes Prostate Cancer More Aggressive Researchers discover a potential therapeutic avenue against an aggressive form of prostate cancer. Prostate cancer is the second most common cancer and the second leading cause of [...]
Nasal Vaccines: Stopping the COVID-19 Virus Before It Reaches the Lungs
The Pfizer-BioNTech and Moderna mRNA vaccines have played a large role in preventing deaths and severe infections from COVID-19. But researchers are still in the process of developing alternative approaches to vaccines to improve [...]
NASA Tracking a Huge, Growing Anomaly in Earth’s Magnetic Field – with video
NASA is actively monitoring a strange anomaly in Earth's magnetic field: a giant region of lower magnetic intensity in the skies above the planet, stretching out between South America and southwest Africa. This vast, developing [...]
New, Better Models Show How Infectious Diseases Like COVID-19 Spread
Infectious diseases such as COVID-19 can spread rapidly across the globe. Models that can predict how such diseases spread will strengthen national surveillance systems and improve public health decision-making. The COVID-19 pandemic has emphasized the [...]
Human Antibodies Discovered That Can Block Multiple Coronaviruses Including COVID-19
Results from a Scripps Research and UNC team pave the way for a vaccine and therapeutic antibodies that could be stockpiled to fight future coronavirus pandemics. A team of scientists from Scripps Research and [...]
Nanotechnology could be used to treat lymphedema
The human body is made up of thousands of tiny lymphatic vessels that ferry white blood cells and proteins around the body, like a superhighway of the immune system. It's remarkably efficient, but if [...]
DNA Nanotechnology Tools – From Design to Applications
Suite of DNA nanotechnology devices engineered to overcome specific bottlenecks in the development of new therapies, diagnostics, and understanding of molecular structures. DNA nanostructures with their potential for cell and tissue permeability, biocompatibility, and [...]
Regenerating bone with deer antler stem cells
Scientists from a collection of Chinese research institutions collaborated on a study of organ regeneration in mammals, finding deer antler blastema progenitor cells are a possible source of conserved regeneration cells in higher vertebrates. [...]
AI Takes On Cancer: Analysis of Mutations Could Lead to Improved Therapy
Cancer is a complex and diverse disease, and its range of associated mutations is vast. The combination of these genomic changes in an individual is referred to as their “mutational landscape.” These landscapes vary [...]
Exposing tumours to bacteria converts immune cells to cancer killers
New research on inflammation could lead to better treatments to improve outcomes for people with advanced or previously untreatable cancers. Introducing bacteria to a tumour’s microenvironment creates a state of acute inflammation that triggers [...]
Smart nanotechnology for more accurate delivery of insulin
More efficient and longer lasting glucose-responsive insulin that eliminates the need for people with type 1 diabetes to measure their glucose levels could be a step closer thanks to a Monash University-led project. Published [...]
Efficiently Harvesting Rare Earth Elements From Wastewater Using Exotic Bacteria
The novel strains of cyanobacteria exhibit a fast and efficient “biosorption” of rare earth elements, making recycling possible. Rare earth elements (REEs) are a set of 17 metallic elements that possess similar chemical properties. [...]
Resisting Treatment: Cancer Cells Shrink or Super-Size To Survive
A new approach to image analysis has uncovered how cancer cells manipulate their size as a means of resisting treatment. Researchers have discovered that cancer cells are capable of either shrinking or super-size themselves [...]
New Research Explains Why Children Avoid Severe COVID-19 Symptoms
According to new research, children exhibit a robust initial immune response to the coronavirus, however, they are unable to transfer this response to long-lasting memory T cells like adults do. Researchers led by scientists [...]
Scientists Unravel Protein Map of Mitochondria
A new study sheds light on the organization of proteins within mitochondria. Mitochondria, the “powerhouses” of cells, play a crucial role in the energy production of organisms and are involved in various metabolic and [...]