While PROTACs might not be the topic of conversation at high society cocktail parties, or merit cover stories in glamor magazines, they’re certainly shaking up the drug discovery industry. PROTAC® degraders, together with related compounds like molecular glues and LYTACs, are the basic tools for a targeted protein degradation strategy. Research in this field is advancing rapidly, enabling the development of therapies for disease targets disease targets previously thought to be “undruggable”. This blog post provides an overview of PROTACs based on frequently asked questions.Continue reading “PROTACs: Just the FAQs”
With use and time things wear out. Tires get worn on a car, and you have the old tires removed, recycled, and replaced with new ones. Sometimes a part or piece of something isn’t made properly. For instance, if you are assembling a piece of furniture and you find a screw with no threads, you throw it out and get a screw that was made properly. The same thing holds true for cells. Components wear out (like tires) or get improperly made (a screw with no threads), or they simply have a limited lifetime so that they are available in the cell only when needed. These used and worn components need to be removed from the cell. One system that allows cells to recycle components and remove old or improperly functioning proteins is the Ubiquitin-Proteasome System (UPS). The UPS system relies on a series of small peptide tags, ubiquitin, to mark a protein for degradation. Researchers are now harnessing the UPS to target aberrant proteins in diseased cells through PROteolysis TArgeting Chimeras or PROTACs. PROTACs hold promise as highly efficacious therapeutics that can be directed to eliminate only a single protein. To take full advantage of the power of PROTACs, researchers need to understand the molecular underpinnings that are responsible for successful protein degradation. Here we review a paper that seeks to develop a computer model for predicting whether PROTAC ternary complex formation leads to ubiquitination and successful degradation of a target protein.
Addressing the Intractable Target
Research to understand diseases including cancers, neurodegeneration, and auto-immune conditions has revealed that in many disease states, affected cells produce growth factors or enzymes that are constitutively active (“always on”). These proteins are targets for small molecule inhibitors that bind specific sites preventing the constitutive activity or signaling. More recently, biologics, or protein-based therapeutics, including monoclonal antibodies (mAb), have been developed that can bind and block inappropriate signaling pathways, especially those that allow cancer cells to escape immune system surveillance.
Unfortunately, up to 85% of targets have proven intractable to small molecule inhibitors, or they are not suitable for a biologics approach. Oftentimes, the target protein doesn’t have a great place to bind a small molecule, so even though inhibitors might exist they cannot bind well enough to be effective. Or, as in the case of many cancers, the diseased cell manages to overcome the effect of the inhibitor by overexpressing the target. Still other aberrant proteins associated with diseases haven’t gained function to cause a disease; they have instead, lost function, so designing an inhibitor of the protein is not a workable strategy. Enter the PROTAC.Continue reading “Using Structural Computation Models to Predict Productive PROTAC Ternary Complexes”
G protein-coupled receptors (GPCRs) comprise a large group of cell surface receptors, characterized by the unique structural property of crossing the cell membrane seven times. They respond to a diverse group of signaling molecules, such as peptides, neurotransmitters, cytokines, hormones and other small molecules (1). Upon activation, GPCRs interact with GTP-binding (G) proteins and arrestins to regulate a wide variety of signaling pathways. This broad range of functions makes GPCRs attractive targets for drug discovery. The importance of GPCR research was highlighted in 2012, with the Nobel Prize in chemistry being awarded to Robert Lefkowitz and Brian Kobilka “for studies of G-protein–coupled receptors”.
Based on structure and function, GPCRs are categorized into six classes, A–F. The class A GPCRs, or rhodopsin-like receptors, have been studied extensively due to their association with many types of diseases (2). Within the class A GPCRs is a group that share a highly conserved structural motif (3) and respond to chemokines—small “chemotactic cytokines” that stimulate cell migration, especially that of white blood cells (4). A subfamily of class A GPCRs respond to chemokines that have two cysteine residues near the N-terminus, known as CC chemokines. GPCRs activated by CC chemokines are called CC chemokine receptors or CCRs, and these interactions have been implicated in both pro- and anti-cancer pathways (5).Continue reading “GPCRs and PROTACs: New Approaches for Designing More Effective Drug Candidates”
Targeting a single protein and making it disappear from the cell is quite the magic trick, and there are various molecular tools available for this task. You can use RNA interference, which prevents a protein from being made, inhibitors that bind the protein, rendering it unavailable for use or even gene editing tools like CRISPR that can remove it from the genome. But did you know that you can target an existing protein for destruction, using the cell’s own garbage disposal system to degrade the protein? All you need is a molecule that can connect your protein to one with a role in cellular protein degradation and your protein can be destroyed.Continue reading “PROTACs, PHOTACs and LYTACs: How to Target a Protein for Degradation”