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Molecular glue refers to small molecules that enhance or stabilize protein-protein interactions within cells. These compounds can either induce new interactions or strengthen existing ones, offering a unique approach to drug discovery. They are particularly useful for targeting proteins that were previously considered “undruggable,” and have potential applications in treating diseases like cancer and neurodegenerative disorders.
Mechanism of Action:
– Induced Proximity: Molecular glues bind to one protein, altering its surface to create a new binding site or enhance an existing one. This allows it to interact with another protein that it wouldn’t normally bind to strongly—or at all.
– Formation of Ternary Complexes: These molecules act as a bridge, forming a complex that includes the glue molecule and the two interacting proteins.
– Targeted Protein Degradation: Some molecular glues recruit E3 ubiquitin ligases to tag a target protein with ubiquitin. This tag signals the proteasome (the cell’s protein degradation machinery) to break down the target protein. This is particularly useful for degrading “undruggable” proteins.Outcomes:
– Stabilization of Protein-Protein Interactions: They can strengthen weak interactions, enhancing normal protein functions or creating new ones.
– Inhibition of Protein Function: By inducing interactions, molecular glues might block a protein’s active site or prevent it from binding to its natural partners.Applications:
– Drug Discovery: They are pivotal in developing therapies for diseases like cancer, autoimmune disorders, and neurodegenerative conditions.
– Chemical Biology: Used to study protein interactions and pathways.Examples:
– Thalidomide and its analogs (Lenalidomide, Pomalidomide): These drugs recruit E3 ligases to degrade specific transcription factors, aiding in cancer treatment.
– Cyclosporin A and FK506: Immunosuppressants that form complexes with proteins to inhibit immune responses.
– Rapamycin: Stabilizes interactions between proteins to block cell growth signals.Advantages:
1. Targeting “Undruggable” Proteins: Molecular glues can modulate proteins that lack traditional binding sites, making them valuable for addressing previously “undruggable” targets.2. Catalytic Efficiency: A single molecule of molecular glue can induce the degradation of multiple target protein molecules, amplifying its therapeutic effect.
3. Small Size: Their compact structure often leads to better cell permeability, oral bioavailability, and the ability to cross the blood-brain barrier.
4. Versatility: They can stabilize or induce protein-protein interactions, leading to diverse therapeutic outcomes, such as targeted protein degradation or functional enhancement.
5. Broad Applications: Useful in treating cancer, autoimmune diseases, and neurodegenerative disorders, as well as in chemical biology for studying protein interactions.
Limitations:
1. Discovery Challenges: Identifying effective molecular glues often relies on serendipity or sophisticated screening methods, making the discovery process complex and resource-intensive.2. Predictability Issues: It is difficult to predict how a small molecule will alter protein surfaces to induce new interactions, complicating the design process.
3. Limited Targets: While they expand the range of druggable proteins, not all proteins can be targeted by molecular glues, and their applicability is still being explored.
4. Potential Off-Target Effects: Inducing unintended protein-protein interactions could lead to undesirable side effects or toxicity.
5. Chemical Sensitivity: Molecular glues are highly sensitive to chemical modifications, which can affect their activity and stability.
Despite these challenges, molecular glues represent a groundbreaking approach in modern drug development.
Answered using Microsoft Copilot.
A reader may like to know the story from the beginning:
Single-cell sequencing – Wikipedia
Spatial transcriptomics – Wikipedia
ALK mutation refers to a change in the ALK gene, which can lead to the development of cancer. ALK stands for anaplastic lymphoma kinase, and it is a gene that provides instructions for making a protein that is involved in cell growth and division. Mutations in the ALK gene can cause the protein to be overactive, leading to uncontrolled cell growth and the development of cancer. ALK mutations have been found in several types of cancer, including non-small cell lung cancer, neuroblastoma, and anaplastic large cell lymphoma. There are treatments available that target ALK mutations in cancer cells, such as ALK inhibitors. These drugs can help to slow or stop the growth of cancer cells with an ALK mutation.
Smoking is indeed the number one cause of lung cancer. However, about 20% of lung cancer deaths occur in people who have never smoked, according to the American Cancer Society. Researchers are working to understand how and why lung cancer develops in non-smokers. They have found that non-smokers have a very different landscape of genetic changes in their cancer than smokers do.
Lung cancers found in never-smokers are more likely to have certain biomarkers, such as EGFR or ALK mutations, which can be treated through drugs designed to target those specific mutations. On the other hand, immune targets, such as PD-L1, a protein targeted by immune checkpoint inhibitors, are more common in tumors caused by smoking.
There are also other factors that can contribute to the development of lung cancer in non-smokers. These include exposure to radon, secondhand smoke, air pollution, or other factors such as asbestos, diesel exhaust or certain other chemicals.
It is important to note that not all smokers develop lung cancer. The risk of developing lung cancer depends on many factors, including the amount and duration of smoking, genetics, and exposure to other risk factors.
The terms “precision medicine” and “personalized medicine” are often used interchangeably, but there is a subtle difference between the two.
Precision medicine is an approach to healthcare that uses information about an individual’s genes, environment, and lifestyle to tailor medical decisions, practices, interventions, and/or products to the individual patient.
Personalized medicine is a broader term that encompasses precision medicine, but also includes other approaches to tailoring healthcare to the individual patient, such as using patient preferences and values.
In other words, precision medicine is a subset of personalized medicine that focuses on using genetic information to make more precise medical decisions. Personalized medicine, on the other hand, is a broader approach that can also include factors such as environment, lifestyle, and patient preferences.
For example, precision medicine uses genetic information to select the best cancer treatment for a patient, while personalized medicine uses in addition the patient preferences to choose a treatment that is acceptable to the patient.
Both precision medicine and personalized medicine are still emerging fields, and there is still much research to be done. However, these approaches have the potential to revolutionize healthcare by providing more effective and tailored treatments for patients.
VHL syndrome (Von Hippel-Lindau syndrome) is an inherited disorder characterized by the formation of tumors and fluid-filled sacs (cysts) in many different parts of the body. Tumors may be either noncancerous or cancerous and most frequently appear during young adulthood; however, the signs and symptoms of von Hippel-Lindau syndrome can occur throughout life. In families with a medical history of VHL syndrome, the presence of one tumor associated with the disorder is considered diagnostic.
Genetic testing involves studying the VHL gene for disease-causing changes (variants or mutations). All that’s needed for this test is a blood sample.
The term originates from the German words wandern (‘to hike’) and Lust (‘desire’), literally translated as ‘enjoyment of hiking’. Wanderlust may reflect an intense urge for self-development by experiencing the unknown, confronting unforeseen challenges, getting to know unfamiliar cultures, ways of life and behaviors.